Novel spiro compounds useful as inhibitors of stearoyl-coenzyme a delta-9 desaturase

ABSTRACT

Heteroaromatic compounds of structural formula (I) are selective inhibitors of stearoyl-coenzyme A delta-9 desaturase (SCD1) relative to other known stearoyl-coenzyme A desaturases. The compounds of the present invention are useful for the prevention and treatment of conditions related to abnormal lipid synthesis and metabolism, including cardiovascular disease, such as atherosclerosis; obesity; diabetes; neurological disease; metabolic syndrome; insulin resistance; and liver steatosis.

FIELD OF THE INVENTION

The present invention relates to heteroaromatic compounds which areinhibitors of stearoyl-coenzyme A delta-9 desaturase (SCD) and the useof such compounds to control, prevent and/or treat conditions ordiseases mediated by SCD activity. The compounds of the presentinvention are useful for the control, prevention and treatment ofconditions and diseases related to abnormal lipid synthesis andmetabolism, including cardiovascular disease, such as atherosclerosis;obesity; diabetes; neurological disease; metabolic syndrome; insulinresistance; cancer; and hepatic steatosis.

BACKGROUND OF THE INVENTION

At least three classes of fatty acyl-coenzyme A (CoA) desaturases(delta-5, delta-6 and delta-9 desaturases) are responsible for theformation of double bonds in mono- and polyunsaturated fatty acyl-CoAsderived from either dietary sources or de novo synthesis in mammals. Thedelta-9 specific stearoyl-CoA desaturases (SCDs) catalyze therate-limiting formation of the cis-double bond at the C9-C10 position inmonounsaturated fatty acyl-CoAs. The preferred substrates arestearoyl-CoA and palmitoyl-CoA, with the resulting oleoyl andpalmitoleoyl-CoA as the main components in the biosynthesis ofphospholipids, triglycerides, cholesterol esters and wax esters (Dobrzynand Natami, Obesity Reviews, 6: 169-174 (2005)).

The rat liver microsomal SCD protein was first isolated andcharacterized in 1974 (Strittmatter et al., PNAS, 71: 4565-4569 (1974)).A number of mammalian SCD genes have since been cloned and studied fromvarious species. For example, two genes have been identified from rat(SCD1 and SCD2, Thiede et al., J. Biol. Chem., 261, 13230-13235 (1986)),Mihara, K., J. Biochem. (Tokyo), 108: 1022-1029 (1990)); four genes frommouse (SCD1, SCD2, SCD3 and SCD4) (Miyazaki et al., J. Biol. Chem., 278:33904-33911 (2003)); and two genes from human (SCD1 and ACOD4 (SCD2)),(Zhang, et al., Biochem. J., 340: 255-264 (1991); Beiraghi, et al.,Gene, 309: 11-21 (2003); Zhang et al., Biochem. J., 388: 135-142(2005)). The involvement of SCDs in fatty acid metabolism has been knownin rats and mice since the 1970's (Oshino, N., Arch. Biochem. Biophys.,149: 378-387 (1972)). This has been further supported by the biologicalstudies of a) Asebia mice that carry the natural mutation in the SCD1gene (Zheng et al., Nature Genetics, 23: 268-270 (1999)), b) SCD1-nullmice from targeted gene deletion (Ntambi, et al., PNAS, 99: 11482-11486(2002), and c) the suppression of SCD1 expression during leptin-inducedweight loss (Cohen et al., Science, 297: 240-243 (2002)). The potentialbenefits of pharmacological inhibition of SCD activity has beendemonstrated with anti-sense oligonucleotide inhibitors (ASO) in mice(Jiang, et al., J. Clin. Invest., 115: 1030-1038 (2005)). ASO inhibitionof SCD activity reduced fatty acid synthesis and increased fatty acidoxidation in primary mouse hepatocytes. Treatment of mice with SCD-ASOsresulted in the prevention of diet-induced obesity, reduced bodyadiposity, hepatomegaly, steatosis, postprandial plasma insulin andglucose levels, reduced de novo fatty acid synthesis, decreased theexpression of lipogenic genes, and increased the expression of genespromoting energy expenditure in liver and adipose tissues. Thus, SCDinhibition represents a novel therapeutic strategy in the treatment ofobesity and related metabolic disorders.

There is compelling evidence to support that elevated SCD activity inhumans is directly implicated in several common disease processes. Forexample, there is an elevated hepatic lipogenesis to triglyceridesecretion in non-alcoholic fatty liver disease patients (Diraison, etal., Diabetes Metabolism, 29: 478-485 (2003)); Donnelly, et al., J.Clin. Invest., 115: 1343-1351 (2005)). Elevated SCD activity in adiposetissue is closely coupled to the development of insulin resistance(Sjogren, et al., Diabetologia, 51(2): 328-35 (2007)). The postprandialde novo lipogenesis is significantly elevated in obese subjects(Marques-Lopes, et al., American Journal of Clinical Nutrition, 73:252-261 (2001)). Knockout of the SCD gene ameliorates Metabolic Syndromeby reducing plasma triglycerides, reducing weight gain, increasinginsulin sensitivity, and reduces hepatic lipid accumulation (MacDonald,et al., Journal of Lipid Research, 49(1): 217-29 (2007)). There is asignificant correlation between a high SCD activity and an increasedcardiovascular risk profile including elevated plasma triglycerides, ahigh body mass index and reduced plasma HDL (Attie, et al., J. LipidRes., 43: 1899-1907 (2002)). SCD activity plays a key role incontrolling the proliferation and survival of human transformed cells(Scaglia and Igal, J. Biol. Chem., (2005)). RNA interference of SCD-1reduces human tumor cell survival (Morgan-Lappe, et al., CancerResearch, 67(9): 4390-4398 (2007)).

Other than the above mentioned anti-sense oligonucleotides, inhibitorsof SCD activity include non-selective thia-fatty acid substrate analogs[B. Behrouzian and P. H. Buist, Prostaglandins, Leukotrienes, andEssential Fatty Acids, 68: 107-112 (2003)], cyclopropenoid fatty acids(Raju and Reiser, J. Biol. Chem., 242: 379-384 (1967)), certainconjugated long-chain fatty acid isomers (Park, et al., Biochim.Biophys. Acta, 1486: 285-292 (2000)), and a series of heterocyclicderivatives disclosed in published international patent applicationpublications WO 2005/011653, WO 2005/011654, WO 2005/011655, WO2005/011656, WO 2005/011657, WO 2006/014168, WO 2006/034279, WO2006/034312, WO 2006/034315, WO 2006/034338, WO 2006/034341, WO2006/034440, WO 2006/034441, WO 2006/034446, WO 2006/086445; WO2006/086447; WO 2006/101521; WO 2006/125178; WO 2006/125179; WO2006/125180; WO 2006/125181; WO 2006/125194; WO 2007/044085; WO2007/046867; WO 2007/046868; WO 2007/050124; WO 2007/130075; WO2007/136746; and WO 2008/074835, all assigned to Xenon Pharmaceuticals,Inc. SCD inhibitors are also disclosed in the following publishedinternational patent application publications: WO 2008/074835; WO2008/074824; WO 2008/036715; WO 2008/044767; WO 2008/029266; WO2008/062276; and WO 2008/127349.

A number of international patent applications assigned to Merck FrosstCanada Ltd. that disclose SCD inhibitors useful for the treatment ofobesity and Type 2 diabetes have also published: WO 2006/130986 (14 Dec.2006); WO 2007/009236 (25 Jan. 2007); WO 2007/056846 (24 May 2007); WO2007/071023 (28 Jun. 2007); WO 2007/134457 (29 Nov. 2007); WO2007/143823 (21 Dec. 2007); WO 2007/143824 (21 Dec. 2007); WO2008/017161 (14 Feb. 2008); WO 2008/046226 (24 Apr. 2008); WO2008/064474 (5 Jun. 2008); and US 2008/0182838 (31 Jul. 2008).

WO 2008/003753 (assigned to Novartis) discloses a series ofpyrazolo[1,5-a]pyrimidine analogs as SCD inhibitors; WO 2007/143697 andWO 2008/024390 (assigned to Novartis and Xenon Pharmaceuticals) discloseheterocyclic derivatives as SCD inhibitors; and WO 2008/096746 (assignedto Takeda Pharmaceutical) and WO 2008/056687 (assigned to Daiichi)disclose spiro compounds as SCD inhibitors.

Small molecule SCD inhibitors have also been described by (a) G. Liu, etal., “Discovery of Potent, Selective, Orally Bioavailable SCD1Inhibitors,” in J. Med. Chem., 50: 3086-3100 (2007); (b) H. Zhao, etal., “Discovery of 1-(4-phenoxypiperidin-1-yl)-2-arylaminoethanone SCD1inhibitors,” Bioorg. Med. Chem. Lett., 17: 3388-3391 (2007); (c) Z. Xin,et al., “Discovery of piperidine-aryl urea-based stearoyl-CoA desaturase1 inhibitors,” Bioorg. Med. Chem. Lett., 18: 4298-4302 (2008); and (d)C. S. Li, et al., “Thiazole analog as stearoyl-CoA desaturase 1inhibitor,” Bioorg. Med. Chem. Lett., 19: 5214-5217 (2009) andreferences therein.

The present invention is concerned with novel heteroaromatic compoundsas inhibitors of stearoyl-CoA delta-9 desaturase which are useful in thetreatment and/or prevention of various conditions and diseases mediatedby SCD activity including those related, but not limited, to elevatedlipid levels, as exemplified in non-alcoholic fatty liver disease,cardiovascular disease, obesity, diabetes, metabolic syndrome, andinsulin resistance.

The role of stearoyl-coenzyme A desaturase in lipid metabolism has beendescribed by M. Miyazaki and J. M. Ntambi, Prostaglandins, Leukotrienes,and Essential Fatty Acids, 68: 113-121 (2003). The therapeutic potentialof the pharmacological manipulation of SCD activity has been describedby A. Dobrzyn and J. M. Ntambi, in “Stearoyl-CoA desaturase as a newdrug target for obesity treatment,” Obesity Reviews, 6: 169-174 (2005).

SUMMARY OF THE INVENTION

The present invention relates to heteroaromatic compounds of structuralformula I:

These heteroaromatic compounds are effective as inhibitors of SCD. Theyare therefore useful for the treatment, control or prevention ofdisorders responsive to the inhibition of SCD, such as diabetes, insulinresistance, lipid disorders, obesity, atherosclerosis, metabolicsyndrome, and cancer.

The present invention also relates to pharmaceutical compositionscomprising the compounds of the present invention and a pharmaceuticallyacceptable carrier.

The present invention also relates to methods for the treatment,control, or prevention of disorders, diseases, or conditions responsiveto inhibition of SCD in a subject in need thereof by administering thecompounds and pharmaceutical compositions of the present invention.

The present invention also relates to methods for the treatment,control, or prevention of Type 2 diabetes, insulin resistance, obesity,lipid disorders, atherosclerosis, metabolic syndrome, and cancer byadministering the compounds and pharmaceutical compositions of thepresent invention.

The present invention also relates to methods for the treatment,control, or prevention of obesity by administering the compounds of thepresent invention in combination with a therapeutically effective amountof another agent known to be useful to treat the condition.

The present invention also relates to methods for the treatment,control, or prevention of Type 2 diabetes by administering the compoundsof the present invention in combination with a therapeutically effectiveamount of another agent known to be useful to treat the condition.

The present invention also relates to methods for the treatment,control, or prevention of insulin resistance by administering thecompounds of the present invention in combination with a therapeuticallyeffective amount of another agent known to be useful to treat thecondition.

The present invention also relates to methods for the treatment,control, or prevention of atherosclerosis by administering the compoundsof the present invention in combination with a therapeutically effectiveamount of another agent known to be useful to treat the condition.

The present invention also relates to methods for the treatment,control, or prevention of lipid disorders by administering the compoundsof the present invention in combination with a therapeutically effectiveamount of another agent known to be useful to treat the condition.

The present invention also relates to methods for the treatment,control, or prevention of metabolic syndrome by administering thecompounds of the present invention in combination with a therapeuticallyeffective amount of another agent known to be useful to treat thecondition.

The present invention also relates to methods for the treatment,control, or prevention of cancer by administering the compounds of thepresent invention in combination with a therapeutically effective amountof another agent known to be useful to treat the condition.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is concerned with heteroaromatic compounds usefulas inhibitors of SCD. Compounds of the present invention are describedby structural formula I:

or a pharmaceutically acceptable salt thereof; whereinA is selected from the group consisting of:

g is a single bond or a double bond;J and K are each independently selected from the group consisting of: S,O, NH, CH and CH₂, wherein each NH is unsubstituted or substituted withR^(g), and wherein each CH and CH₂ is unsubstituted or substituted withR², provided that when g is a single bond at least one of J and K is CH₂unsubstituted or substituted with R², and further provided that when gis a double bond then both J and K are CH;L and M are each independently selected from the group consisting of: S,O, NH and CH₂, wherein each NH is unsubstituted or substituted withR^(g), and wherein each CH₂ is unsubstituted or substituted with R²;T, U, V and W are each independently selected from N and CH, whereineach CH is unsubstituted or substituted with R³, provided that at leasttwo of T, U, V and W are CH;X is CH₂, wherein CH₂ is unsubstituted or substituted with R²;Y is independently selected from the group consisting of: O, NH and CH₂,wherein each NH is unsubstituted or substituted with R^(g), and whereineach CH₂ is unsubstituted or substituted with R²;Z is independently selected from the group consisting of: S, S(O),S(O)₂, O, NH and CH₂, wherein each NH is unsubstituted or substitutedwith R^(g), and wherein each CH₂ is unsubstituted or substituted withR²;B is a 5 membered heteroaryl ring containing 1, 2 or 3 heteroatomsselected from NH, O and S, wherein any CH is unsubstituted orsubstituted with one substituent selected from R^(a), and wherein any NHis unsubstituted or substituted with one substituent selected fromR^(b);each R¹ is independently selected from the group consisting of:hydrogen, halogen, and C₁₋₃ alkyl, wherein alkyl is unsubstituted orsubstituted with one to three substituents independently selected fromhalogen and hydroxy;each R² is independently selected from the group consisting of:

-   -   (1) hydrogen,    -   (2) halogen,    -   (3) oxo,    -   (4) C₁₋₆ alkyl,    -   (5) (CH₂)_(n)OR^(e),    -   (6) (CH₂)_(n)N(R^(e))₂,    -   (7) (CH₂)_(n)C≡N,    -   (8) (CH₂)_(n)COR^(e), and    -   (9) (CH₂)_(n)S(O)_(q)R^(e),        wherein alkyl is unsubstituted or substituted with hydroxy or        one to three halogens, and wherein any CH₂ in R² is        unsubstituted or substituted with one to two groups        independently selected from halogen, hydroxy, and C₁₋₄ alkyl        unsubstituted or substituted with one to five fluorines;        each R³ is independently selected from the group consisting of:    -   (1) hydrogen,    -   (2) halogen,    -   (3) —C₁₋₆ alkyl,    -   (4) —C₁₋₆ alkenyl,    -   (5) —OC₁₋₆ alkyl,    -   (6) (CH₂)_(n)OR^(e),    -   (7) (CH₂)_(n)N(R^(e))₂,    -   (8) (CH₂)_(n)C≡N,    -   (9) (CH₂)_(n)COR^(e), and    -   (10) (CH₂)_(n)S(O)_(q)R^(e),        wherein alkyl is unsubstituted or substituted with one to three        substituents selected from: hydroxy, halogen, C₁₋₄ alkyl, C₃₋₆        cycloalkyl, C₂₋₅ cycloheteroalkyl, aryl, and heteroaryl wherein        alkyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl are        unsubstituted or substituted with one to three substituents        selected from: halogen, hydroxy, and C₁₋₄ alkyl unsubstituted or        substituted with one to five fluorines, and wherein any CH₂ in        R³ is unsubstituted or substituted with one to two groups        independently selected from halogen, hydroxy, and C₁₋₄ alkyl        unsubstituted or substituted with one to five fluorines;        R⁴ is selected from the group consisting of:

each R^(a) is independently selected from the group consisting of:

-   -   (1) hydrogen,    -   (2) halogen,    -   (3) cyano,    -   (4) C₁₋₄ alkyl, unsubstituted or substituted with one to five        fluorines,    -   (5) C₁₋₄ alkoxy, unsubstituted or substituted with one to five        fluorines,    -   (6) C₁₋₄ alkylthio, unsubstituted or substituted with one to        five fluorines,    -   (7) C₁₋₄ alkylsulfonyl,    -   (8) —CO₂H,    -   (9) C₁₋₄ alkyloxycarbonyl, and    -   (10) C₁₋₄ alkylcarbonyl;        each R^(b) is independently selected from the group consisting        of:    -   (1) hydrogen, and    -   (2) C₁₋₄ alkyl,        wherein alkyl is unsubstituted or substituted with one to five        fluorines;        each R^(c) is independently selected from the group consisting        of:    -   (1) —(CH₂)_(m)CO₂H,    -   (2) —(CH₂)_(m)CO₂C₁₋₃ alkyl,    -   (3) —(CH₂)_(m)—NR^(b)—(CH₂)_(p)CO₂H,    -   (4) —(CH₂)_(m)—NR^(b)—(CH₂)_(p)CO₂C₁₋₃ alkyl,    -   (5) —(CH₂)_(m)—O—(CH₂)_(p)CO₂H,    -   (6) —(CH₂)_(m)—O—(CH₂)_(p)CO₂C₁₋₃ alkyl,    -   (7) —(CH₂)_(m)—S—(CH₂)_(p)CO₂H, and    -   (8) —(CH₂)_(m)—S—(CH₂)_(p)CO₂C₁₋₃ alkyl,        wherein any CH₂ in R^(e) is unsubstituted or substituted with        one to two groups independently selected from halogen, hydroxy,        and C₁₋₄ alkyl unsubstituted or substituted with one to five        fluorines;        each R^(d) is independently selected from the group consisting        of:    -   (1) —(CH₂)_(n)CO₂H,    -   (2) —(CH₂)_(n)CO₂C₁₋₃ alkyl,    -   (3) —(CH₂)_(n)—NR^(b)—(CH₂)_(p)CO₂H,    -   (4) —(CH₂)_(n)—NR^(b)—(CH₂)_(p)CO₂C₁₋₃ alkyl,    -   (5) —(CH₂)_(n)—O—(CH₂)_(p)CO₂H,    -   (6) —(CH₂)_(n)—O—(CH₂)_(p)CO₂C₁₋₃ alkyl,    -   (7) —(CH₂)_(n)—S—(CH₂)_(p)CO₂H, and    -   (8) —(CH₂)_(n)—S—(CH₂)_(p)CO₂C₁₋₃ alkyl,        wherein any CH₂ in R^(d) is unsubstituted or substituted with        one to two groups independently selected from the group        consisting of: halogen, hydroxy, and C₁₋₄ alkyl unsubstituted or        substituted with one to five fluorines;        each R^(e) is independently selected from the group consisting        of:    -   (1) hydrogen, and    -   (2) C₁₋₆ alkyl,        wherein alkyl is unsubstituted or substituted with one to three        substituents independently selected from the group consisting        of: halogen, cyano, —C₁₋₄ alkoxy, —C₁₋₄ alkylthio, —C₁₋₄        alkylsulfonyl, —CO₂H, and —CO₂C₁₋₄ alkyl;        each R^(g) is independently selected from the group consisting        of:    -   (1) hydrogen, and    -   (2) C₁₋₆ alkyl;        m is an integer from 1 to 3;        n is an integer from 0 to 3;        p is an integer from 1 to 3;        q is an integer from 1 to 2;        t is an integer from 0 to 8;        d is an integer from 0 to 2; and        e is an integer from 0 to 2,        provided that d+e is 2.

In one embodiment of the present invention, A is selected from the groupconsisting of

In a class of this embodiment, A is selected from the group consistingof:

In another class of this embodiment, A is selected from the groupconsisting of:

In another class of this embodiment, A is selected from the groupconsisting of:

In another class of this embodiment, A is selected from the groupconsisting of:

In another class of this embodiment, A is selected from the groupconsisting of:

In another class of this embodiment, A is selected from the groupconsisting of:

In another class of this embodiment, A is selected from the groupconsisting of:

In another class of this embodiment, A is:

In another class of this embodiment, A is:

In another class of this embodiment, A is:

In another class of this embodiment, A is:

In another class of this embodiment, A is:

In another class of this embodiment, A is selected from the groupconsisting of:

In another embodiment of the present invention, B is a 5-memberedheteroaryl ring containing 1, 2 or 3 heteroatoms selected from NH, O andS, wherein any CH is unsubstituted or substituted with one substituentselected from R^(a), and wherein any NH is unsubstituted or substitutedwith one substituent selected from R^(b).

In another class of this embodiment B is a 5-membered heteroaryl ringcontaining 2 or 3 heteroatoms selected from NH, O and S, wherein any CHis unsubstituted or substituted with one substituent selected fromR^(a), and wherein NH is unsubstituted or substituted with onesubstituent selected from R^(b).

In another class of this embodiment, B is selected from the groupconsisting of:

In another class of this embodiment, B is selected from the groupconsisting of:

In another class of this embodiment, B is selected from the groupconsisting of:

In another class of this embodiment, B is selected from the groupconsisting of:

In another class of this embodiment, B is selected from the groupconsisting of:

In another class of this embodiment, B is selected from the groupconsisting of:

In another embodiment of the present invention, B-R⁴ is selected fromthe group consisting of:

In a class of this embodiment, B-R⁴ is

In another class of this embodiment, B-R⁴ is

In yet another class of this embodiment, B-R⁴ is

In another embodiment of the present invention, B-R⁴ is selected fromthe group consisting of:

In a class of this embodiment, B-R⁴ is

In another embodiment of the present invention, J and K are eachindependently selected from the group consisting of: S, O, NH, CH andCH₂, wherein each NH is unsubstituted or substituted with R^(g), andwherein each CH and CH₂ is unsubstituted or substituted with R²,provided that when g is a single bond at least one of J and K is CH₂unsubstituted or substituted with R², and further provided that when gis a double bond then both J and K are CH. In a class of thisembodiment, J and K are each independently selected from the groupconsisting of: O, NH, CH and CH₂, wherein each NH is unsubstituted orsubstituted with R^(g), and wherein each CH and CH₂ is unsubstituted orsubstituted with R², provided that when g is a single bond at least oneof J and K is CH₂ unsubstituted or substituted with R², and furtherprovided that when g is a double bond then both J and K are CH. Inanother class of this embodiment, g is a single bond, J is O and K isCH₂, wherein CH₂ is unsubstituted or substituted with R². In anotherclass of this embodiment, g is a single bond, J is O and K is C═O. Inanother class of this embodiment, g is a single bond, J is CH₂ and K isO, wherein CH₂ is unsubstituted or substituted with R². In another classof this embodiment, g is a single bond, J is CH₂ and K is O. In anotherclass of this embodiment, g is a single bond, J is CH₂ and K is O,wherein CH₂ is unsubstituted or substituted with R². In another class ofthis embodiment, g is a single bond, J is C═O and K is O. In anotherclass of this embodiment, g is a single bond, J and K are CH₂, whereinCH₂ is unsubstituted or substituted with R². In another class of thisembodiment, g is a single bond, J is C═O and K is CH₂. In another classof this embodiment, g is a single bond, J is CH₂ and K is C═O.

In another class of this embodiment, g is a double bond, J and K areselected from N and CH, wherein each NH is unsubstituted or substitutedwith R^(g), and wherein each CH is unsubstituted or substituted with R².In another class of this embodiment, g is a double bond, J and K are CH,wherein each CH is unsubstituted or substituted with R². In anotherclass of this embodiment, g is a double bond, J and K are CH.

In another embodiment of the present invention, L and M are eachindependently selected from the group consisting of: S, O, NH and CH₂,wherein each NH is unsubstituted or substituted with R^(g), and whereineach CH₂ is unsubstituted or substituted with R². In class of thisembodiment, M and L are each independently selected from the groupconsisting of: S, O, NH and CH₂, wherein NH is unsubstituted orsubstituted with R^(g), and wherein CH₂ is unsubstituted or substitutedwith R². In another class of this embodiment, M and L are eachindependently selected from the group consisting of: O, NH and CH₂,wherein NH is unsubstituted or substituted with R^(g), and wherein CH₂is unsubstituted or substituted with R². In another class of thisembodiment, g is a single bond, M and Lure CH₂, wherein CH₂ isunsubstituted or substituted with R². In another class of thisembodiment, g is a single bond, M is C═O and L is CH₂.

In another embodiment of the present invention, T, U, V and W are eachindependently selected from N and CH, wherein CH is unsubstituted orsubstituted with R³. In a class of this embodiment, T, U, V and W areeach CH, wherein CH is unsubstituted or substituted with R³. In anotherclass of this embodiment, T, U, V and W are each independently selectedfrom N and CH, wherein CH is unsubstituted or substituted with R³,provided that at least one of T, U, V and W is N. In another class ofthis embodiment, T, U, V and W are each independently selected from Nand CH, wherein CH is unsubstituted or substituted with R³, providedthat one of T or W is N. In another class of this embodiment, T is N andU, V and W are CH, wherein CH is unsubstituted or substituted with R³.In another class of this embodiment, T, U, V are CH and W is N, whereinCH is unsubstituted or substituted with R³.

In another embodiment of the present invention, X is CH₂, wherein CH₂ isunsubstituted or substituted with one or two substituents selected fromR². In a class of this embodiment of the present invention, X is CH₂.

In another embodiment of the present invention, Y is independentlyselected from the group consisting of: O, NH and CH₂, wherein each NH isunsubstituted or substituted with R^(g), and wherein each CH₂ isunsubstituted or substituted with one or two substituents selected fromR². In a class of this embodiment, Y is CH₂, wherein CH₂ isunsubstituted or substituted with R². In another class of thisembodiment, Y is CH₂.

In another embodiment of the present invention, Z is independentlyselected from the group consisting of: S, S(O), S(O)₂, O, NH and CH₂,wherein each NH is unsubstituted or substituted with R^(g), and whereineach CH₂ is unsubstituted or substituted with R². In a class of thisembodiment, Z is independently selected from the group consisting of: S,O, NH and CH₂, wherein each NH is unsubstituted or substituted withR^(g), and wherein each CH₂ is unsubstituted or substituted with R². Inanother class of this embodiment, Z is independently selected from thegroup consisting of: O, NH and CH₂, wherein each NH is unsubstituted orsubstituted with R^(g), and wherein each CH₂ is unsubstituted orsubstituted with R². In another class of this embodiment, Z isindependently selected from the group consisting of: O and CH₂, whereinCH₂ is unsubstituted or substituted with R². In another class of thisembodiment, Z is independently selected from the group consisting of: Oand CH₂. In another class of this embodiment, Z is CH₂, wherein CH₂ isunsubstituted or substituted with R². In another class of thisembodiment, Z is O.

In another class of this embodiment, X and Y are CH₂ and Z is O, whereineach CH₂ is unsubstituted or substituted with R². In another class ofthis embodiment, X and Y are CH₂ and Z is O. In another class of thisembodiment, X is C═O, Y is CH₂ and Z is O, wherein CH₂ is unsubstitutedor substituted with R². In another class of this embodiment, X is C═O, Yis CH₂ and Z is O. In another class of this embodiment, X is C—OH, Y isCH₂ and Z is O. In another class of this embodiment, X is CH—F, Y is CH₂and Z is O. In another class of this embodiment, X is CH₂, Y is —CH—CH₃and Z is O.

In another class of this embodiment, X is CH₂, Y is NH and Z is O,wherein NH is unsubstituted or substituted with R^(g), and wherein CH₂is unsubstituted or substituted with R². In another class of thisembodiment, X is C═O, Y is NH and Z is O, wherein NH is unsubstituted orsubstituted with R^(g). In another class of this embodiment, X is C═O, Yis NH and Z is O. In another class of this embodiment, X and Z are CH₂,and Y is NH, wherein NH is unsubstituted or substituted with R^(g), andwherein each CH₂ is unsubstituted or substituted with R². In anotherclass of this embodiment, X is C═O, Y is NH and Z is CH₂, wherein NH isunsubstituted or substituted with R^(g), and wherein CH₂ isunsubstituted or substituted with R². In another class of thisembodiment, X is C═O, Y is NH and Z is CH₂.

In another class of this embodiment, Y is O, and X and Z are CH₂,wherein each CH₂ is unsubstituted or substituted with R². In anotherclass of this embodiment, X is C═O, Y is O and Z is CH₂, wherein eachCH₂ is unsubstituted or substituted with R². In another class of thisembodiment, X is C═O, Y is O and Z is CH₂. In another class of thisembodiment, X and Y are CH₂ and Z is S, wherein each CH₂ isunsubstituted or substituted with R². In another class of thisembodiment, X is C═O, Y is CH₂ and Z is S, wherein each CH₂ isunsubstituted or substituted with R². In another class of thisembodiment, X is C═O, Y is CH₂ and Z is S.

In another embodiment of the present invention, each R¹ is independentlyselected from the group consisting of: hydrogen, halogen, and C₁₋₃alkyl, wherein alkyl is unsubstituted or substituted with one to threesubstituents independently selected from halogen and hydroxy. In a classof this embodiment, each R¹ is independently selected from the groupconsisting of: hydrogen, halogen, or C₁₋₃ alkyl. In another class ofthis embodiment, each R¹ is hydrogen.

In another embodiment of the present invention, each R² is independentlyselected from the group consisting of: hydrogen, halogen, oxo, —C₁₋₆alkyl, —OC₁₋₆ alkyl, (CH₂)_(n)OR^(e), (CH₂)_(n)N(R^(e))₂, (CH₂)_(n)C≡N,(CH₂)_(n)COR^(e), and (CH₂)_(n)S(O)_(q)R^(e),

wherein alkyl is unsubstituted or substituted with hydroxy or one tothree halogens; and wherein any CH₂ in R² is unsubstituted orsubstituted with one to two groups independently selected from halogen,hydroxy, and C₁₋₄ alkyl unsubstituted or substituted with one to fivefluorines. In a class of this embodiment, each R² is independentlyselected from the group consisting of: hydrogen, halogen, oxo, —C₁₋₆alkyl, —OC₁₋₆ alkyl, (CH₂)_(n)OR^(e), (CH₂)_(n)N(R^(e))₂, (CH₂)_(n)C≡N,and (CH₂)_(n)COR^(e), wherein alkyl is unsubstituted or substituted withhydroxy or one to three halogens; and wherein any CH₂ in R² isunsubstituted or substituted with one to two groups independentlyselected from halogen, hydroxy, and C₁₋₄ alkyl unsubstituted orsubstituted with one to five fluorines. In a subclass of this class,each R² is independently selected from the group consisting of:hydrogen, halogen, and oxo. In another subclass of this class, each R²is independently selected from the group consisting of: hydrogen, bromo,chloro, fluoro, and oxo. In another subclass of this class, each R² isindependently selected from the group consisting of: hydrogen, and oxo.In another subclass of this class, each R² is hydrogen. In anothersubclass of this class, each R² is oxo. In another class of thisembodiment, each R² is independently selected from the group consistingof: hydrogen, deuterium, halogen, oxo, —C₁₋₆ alkyl, and —OR^(e), whereinalkyl is unsubstituted or substituted with hydroxy or one to threehalogens. In a subclass of this class, each R² is independently selectedfrom the group consisting of: hydrogen, deuterium, halogen, oxo, —C₁₋₆alkyl, and —OH. In another subclass of this class, each R² isindependently selected from the group consisting of: hydrogen,deuterium, fluoro, oxo, —CH₃, and —OH.

In another embodiment of the present invention, each R³ is independentlyselected from the group consisting of: hydrogen, halogen, —C₁₋₆ alkyl,—C₁₋₆ alkenyl, —OC₁₋₆ alkyl, —(CH₂)_(n)OR^(e), —(CH₂)_(n)N(R^(e))₂,—(CH₂)_(n)C≡N, —(CH₂)_(n)COR^(e), and —(CH₂)_(n)S(O)_(q)R^(e), whereinalkyl is unsubstituted or substituted with one to three substituentsselected from: hydroxy, halogen, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₂₋₅cycloheteroalkyl, aryl, and heteroaryl wherein alkyl, cycloalkyl,cycloheteroalkyl, aryl and heteroaryl are unsubstituted or substitutedwith one to three substituents selected from: halogen, hydroxy, and C₁₋₄alkyl unsubstituted or substituted with one to five fluorines, andwherein any CH₂ in R³ is unsubstituted or substituted with one to twogroups independently selected from halogen, hydroxy, and C₁₋₄ alkylunsubstituted or substituted with one to five fluorines. In a class ofthis embodiment, Broader: each R³ is independently selected from thegroup consisting of: hydrogen, halogen, —C₁₋₆ alkyl, —C₁₋₆ alkenyl,—OC₁₋₆ alkyl, and (CH₂)_(n)OR^(e), wherein alkyl is unsubstituted orsubstituted with one to three substituents selected from: hydroxy,halogen, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₂₋₅ cycloheteroalkyl, aryl, andheteroaryl wherein alkyl, cycloalkyl, cycloheteroalkyl, aryl andheteroaryl are unsubstituted or substituted with one to threesubstituents selected from: halogen, hydroxy, and C₁₋₄ alkylunsubstituted or substituted with one to five fluorines. In anotherclass of this embodiment, each R³ is independently selected from thegroup consisting of: hydrogen, halogen, —C₁₋₆ alkyl, —C₁₋₆ alkenyl,—OC₁₋₆ alkyl, and (CH₂)_(n)OR^(e), wherein alkyl is unsubstituted orsubstituted with one to three substituents selected from: hydroxy,halogen, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, and phenyl, wherein alkyl,cycloalkyl, and phenyl are unsubstituted or substituted with one tothree substituents selected from: halogen, hydroxy, and C₁₋₄ alkylunsubstituted or substituted with one to five fluorines. In anotherclass of this embodiment, each R³ is independently selected from thegroup consisting of: hydrogen, halogen, —C₁₋₆ alkyl, —C₁₋₆ alkenyl,—OC₁₋₆ alkyl, and (CH₂)_(n)OR^(e), wherein alkyl is unsubstituted orsubstituted with one to three substituents selected from: hydroxy,halogen, C₁₋₄ alkyl, cyclopropyl and difluoro phenyl. In another classof this embodiment, each R³ is independently selected from the groupconsisting of: hydrogen, Cl, Br, F, I, —CH₃, —CF₃, —CH₂CH₃, —CH═CH₂,—OCH₃, —OCF₃, —OCH₂CH₃, —OCH₂CH₂F, —O(CH₂)₂CH₃, O—CH₂-cyclopropyl,O—CH₂-difluorophenyl, and —OH.

In another class of this embodiment, each R³ is independently selectedfrom the group consisting of: Cl, Br, F, I, —CH₃, —CF₃, —CH₂CH₃,—CH═CH₂, —OCH₃, —OCF₃, —OCH₂CH₃, —OCH₂CH₂F, —O(CH₂)₂CH₃,O—CH₂-cyclopropyl, O—CH₂-difluorophenyl, and —OH.

In another embodiment of the present invention, each R³ is independentlyselected from the group consisting of: hydrogen, Cl, Br, —CH₃, —CF₃, and—OCF₃. In a class of this embodiment, each R³ is independently selectedfrom the group consisting of: Cl, Br, —CH₃, —CF₃, and —OCF₃.

In another embodiment of the present invention, R³ is independentlyselected from the group consisting of: hydrogen, halogen, —C₁₋₆ alkyl,—OC₁₋₆ alkyl, (CH₂)_(n)OR^(e), (CH₂)_(n)N(R^(e))₂, (CH₂)_(n)C≡N,(CH₂)_(n)COR^(e), and (CH₂)_(n)S(O)_(q)R^(e), wherein alkyl isunsubstituted or substituted with hydroxy or one to three halogens; andwherein any CH₂ in R³ is unsubstituted or substituted with one to twogroups independently selected from halogen, hydroxy, and C₁₋₄ alkylunsubstituted or substituted with one to five fluorines. In a class ofthis embodiment, R³ is independently selected from the group consistingof: hydrogen, halogen, —C₁₋₆ alkyl, —OC₁₋₆ alkyl, (CH₂)_(n)OR^(e),(CH₂)_(n)N(R^(e))₂, (CH₂)_(n)C≡N, and (CH₂)_(n)COR^(e), wherein alkyl isunsubstituted or substituted with hydroxy or one to three halogens; andwherein any CH₂ in R³ is unsubstituted or substituted with one to twogroups independently selected from halogen, hydroxy, and C₁₋₄ alkylunsubstituted or substituted with one to five fluorines. In a class ofthis embodiment, R³ is independently selected from the group consistingof: hydrogen, halogen, —C₁₋₆ alkyl, —OH, and —OC₁₋₆ alkyl, wherein alkylis unsubstituted or substituted with hydroxy or one to three halogens;and wherein any CH₂ in R³ is unsubstituted or substituted with one totwo groups independently selected from halogen, hydroxy, and C₁₋₄ alkylunsubstituted or substituted with one to five fluorines. In a subclassof this class, R³ is independently selected from the group consistingof: hydrogen, halogen, —C₁₋₆ alkyl, —OH, and —OC₁₋₆ alkyl. In anothersubclass of this class, R³ is independently selected from the groupconsisting of: hydrogen, halogen, —OH, and —OC₁₋₆ alkyl, wherein alkylis unsubstituted or substituted with hydroxy or one to three halogens,and wherein any CH₂ in R³ is unsubstituted or substituted with one totwo groups independently selected from halogen, hydroxy, —OH, and C₁₋₄alkyl unsubstituted or substituted with one to five fluorines. Inanother subclass of this class, R³ is independently selected from thegroup consisting of: hydrogen, halogen, —OH, and —OC₁₋₆ alkyl. Inanother subclass of this class, R³ is independently selected from thegroup consisting of: hydrogen, halogen, —OH and OCH₃. In anothersubclass of this class, R³ is independently selected from the groupconsisting of: —OH and OCH₃. In another subclass of this class, R³ isindependently selected from the group consisting of: hydrogen, andhalogen. In another subclass of this class, R³ is independently selectedfrom the group consisting of: hydrogen, bromo, chloro and fluoro. Inanother subclass of this class, R³ is independently selected from thegroup consisting of: hydrogen, chloro and fluoro. In another subclass ofthis class, R³ is independently selected from the group consisting of:hydrogen, and chloro. In another subclass of this class, R³ is chloro.In another subclass of this class, R³ is halogen. In another subclass ofthis class, R³ is independently selected from the group consisting of:bromo, chloro and fluoro. In another subclass of this class, R³ isindependently selected from the group consisting of: chloro and fluoro.In another class of this embodiment, R³ is chloro.

In a class of this embodiment, R³ is independently selected from thegroup consisting of: hydrogen, halogen, —C₁₋₆ alkyl, —OC₁₋₆ alkyl,(CH₂)_(n)OR^(e), (CH₂)_(n)N(R^(e))₂, (CH₂)_(n)C≡N, and (CH₂)_(n)COR^(e),wherein alkyl is unsubstituted or substituted with hydroxy or one tothree halogens; and wherein any CH₂ in R³ is unsubstituted orsubstituted with one to two groups independently selected from halogen,hydroxy, and C₁₋₄ alkyl unsubstituted or substituted with one to fivefluorines. In a class of this embodiment, R³ is independently selectedfrom the group consisting of: hydrogen, halogen, —C₁₋₆ alkyl, —OH, and—OC₁₋₆ alkyl, wherein alkyl is unsubstituted or substituted with hydroxyor one to three halogens; and wherein any CH₂ in R³ is unsubstituted orsubstituted with one to two groups independently selected from halogen,hydroxy, and C₁₋₄ alkyl unsubstituted or substituted with one to fivefluorines.

In another embodiment of the present invention, R⁴ is selected from thegroup consisting of: heteroaryl, and cycloheteroalkyl, wherein any NHgroup is unsubstituted or substituted with R^(c), and wherein any CH orCH₂ group is unsubstituted or substituted with 1 to 2 substituentsselected from R^(d). In a class of this embodiment, R⁴ is heteroaryl,wherein any NH group is unsubstituted or substituted with R^(e), andwherein any CH or CH₂ group is unsubstituted or substituted with onesubstituent selected from R^(d). In a class of this embodiment, R⁴ isheteroaryl, wherein any NH group is unsubstituted or substituted withR^(c), and wherein any CH group is unsubstituted or substituted with onesubstituent selected from R^(d). In another class of this embodiment, R⁴is cycloheteroalkyl, wherein any NH group is unsubstituted orsubstituted with R^(c), and wherein any CH or CH₂ group is unsubstitutedor substituted with one substituent selected from R^(d). In anotherclass of this embodiment, R⁴ is cycloheteroalkyl, wherein any NH groupis unsubstituted or substituted with R^(c), and wherein any CH₂ group isunsubstituted or substituted with one to two substituents selected fromR^(d).

In another embodiment of the present invention, R⁴ is selected from thegroup consisting of:

In a class of this embodiment, R⁴ is selected from the group consistingof:

In a class of this embodiment, R⁴ is selected from the group consistingof:

In another class of this embodiment, R⁴ is selected from the groupconsisting of:

In another class of this embodiment, R⁴ is selected from the groupconsisting of:

In another class of this embodiment, R⁴ is:

In another class of this embodiment, R⁴ is selected from the groupconsisting of:

In another class of this embodiment, R⁴ is:

In another embodiment of the present invention, each R^(a) isindependently selected from the group consisting of: hydrogen, halogen,cyano, C₁₋₄ alkyl, unsubstituted or substituted with one to fivefluorines, C₁₋₄ alkoxy, unsubstituted or substituted with one to fivefluorines, C₁₋₄ alkylthio, unsubstituted or substituted with one to fivefluorines, C₁₋₄ alkylsulfonyl, —CO₂H, C₁₋₄ alkyloxycarbonyl, and C₁₋₄alkylcarbonyl. In a class of this embodiment, R^(a) is independentlyselected from the group consisting of: hydrogen, halogen, cyano, andC₁₋₄ alkyl, unsubstituted or substituted with one to five fluorines. Inanother class of this embodiment, R^(a) is independently selected fromthe group consisting of: hydrogen, and C₁₋₄ alkyl, unsubstituted orsubstituted with one to five fluorines. In another class of thisembodiment, R^(a) is hydrogen. In another class of this embodiment,R^(a) is C₁₋₄ alkyl, unsubstituted or substituted with one to fivefluorines. In another class of this embodiment, R^(a) is C₁₋₄ alkyl.

In another embodiment of the present invention, each R^(b) isindependently selected from the group consisting of: hydrogen, and C₁₋₄alkyl, wherein alkyl is unsubstituted or substituted with one to fivefluorines. In a class of this embodiment, R^(b) is hydrogen. In anotherclass of this embodiment, R^(b) is C₁₋₄ alkyl, wherein alkyl isunsubstituted or substituted with one to five fluorines. In anotherclass of this embodiment, R^(b) is C₁₋₄ alkyl.

In another embodiment of the present invention, each R^(c) isindependently selected from the group consisting of: —(CH₂)_(m)CO₂H,—(CH₂)_(m)CO₂C₁₋₃ alkyl, —(CH₂)_(m)—NR^(b)—(CH₂)_(p)CO₂H,—(CH₂)_(m)—NR^(b)—(CH₂)_(p)CO₂C₁₋₃ alkyl, —(CH₂)_(m)—O—(CH₂)_(p)CO₂H,—(CH₂)_(m)—O—(CH₂)_(p)CO₂C₁₋₃ alkyl, —(CH₂)_(m)—S—(CH₂)_(p)CO₂H, and—(CH₂)_(m)—S—(CH₂)_(p)CO₂C₁₋₃ alkyl, wherein any CH₂ in R^(c) isunsubstituted or substituted with one to two groups independentlyselected from halogen, hydroxy, and C₁₋₄ alkyl unsubstituted orsubstituted with one to five fluorines. In another class of thisembodiment, R^(e) is selected from the group consisting of:—(CH₂)_(m)CO₂H, —(CH₂)_(m)CO₂C₁₋₃ alkyl, —(CH₂)_(m)OCOH,—(CH₂)_(m)OCOC₁₋₃ alkyl, —(CH₂)_(m)COH, —(CH₂)_(m)COC₁₋₃ alkyl,—(CH₂)_(m)—NR^(b)—(CH₂)_(p)CO₂H, —(CH₂)_(m)—NR^(b)—(CH₂)_(p)CO₂C₁₋₃alkyl, —(CH₂)_(m)—O—(CH₂)_(p)CO₂H, and —(CH₂)_(m)—O—(CH₂)_(p)CO₂C₁₋₃alkyl, wherein any CH₂ in R^(c) is unsubstituted or substituted with oneto two groups independently selected from halogen, hydroxy, and C₁₋₄alkyl unsubstituted or substituted with one to five fluorines. Inanother class of this embodiment, R^(c) is selected from the groupconsisting of: —(CH₂)_(m)CO₂H, —(CH₂)_(m)CO₂C₁₋₃ alkyl, —(CH₂)_(m)OCOH,—(CH₂)_(m)OCOC₁₋₃ alkyl, —(CH₂)_(m)COH, and —(CH₂)_(m)COC₁₋₃ alkyl,wherein any CH₂ in R^(c) is unsubstituted or substituted with one to twogroups independently selected from halogen, hydroxy, and C₁₋₄ alkylunsubstituted or substituted with one to five fluorines. In anotherclass of this embodiment, R^(c) is selected from the group consistingof: —(CH₂)_(m)CO₂H, —(CH₂)_(m)CO₂C₁₋₃ alkyl, —(CH₂)_(m)OCOH,—(CH₂)_(m)OCOC₁₋₃ alkyl, —(CH₂)_(m)COH, —(CH₂)_(m)COC₁₋₃ alkyl,—(CH₂)_(m)—NR^(b)—(CH₂)_(p)CO₂H, —(CH₂)_(m)—NR^(b)—(CH₂)_(p)CO₂C₁₋₃alkyl, wherein any CH₂ in R^(c) is unsubstituted or substituted with oneto two groups independently selected from halogen, hydroxy, and C₁₋₄alkyl unsubstituted or substituted with one to five fluorines. Inanother class of this embodiment, R^(c) is selected from the groupconsisting of: —(CH₂)_(m)CO₂H, and —(CH₂)_(m)CO₂C₁₋₃ alkyl, wherein anyCH₂ in R^(c) is unsubstituted or substituted with one to two groupsindependently selected from halogen, hydroxy, and C₁₋₄ alkylunsubstituted or substituted with one to five fluorines. In anotherclass of this embodiment, R^(c) is —(CH₂)_(m)CO₂H. In another class ofthis embodiment, R^(c) is —(CH₂)_(q)CO₂C₁₋₃ alkyl.

In another embodiment of the present invention, each R^(d) isindependently selected from the group consisting of: —(CH₂)_(n)CO₂H,—(CH₂)_(n)CO₂C₁₋₃ alkyl, —(CH₂)_(n)—NR^(b)—(CH₂)_(p)CO₂H,—(CH₂)_(n)—NR^(b)—(CH₂)_(p)CO₂C₁₋₃ alkyl, —(CH₂)_(n)—O—(CH₂)_(p)CO₂H,—(CH₂)_(n)—O—(CH₂)_(p)CO₂C₁₋₃ alkyl, —(CH₂)_(n)—S—(CH₂)_(p)CO₂H, and—(CH₂)_(n)—S—(CH₂)_(p)CO₂C₁₋₃ alkyl, wherein any CH₂ in R^(d) isunsubstituted or substituted with one to two groups independentlyselected from the group consisting of: halogen, hydroxy, and C₁₋₄ alkylunsubstituted or substituted with one to five fluorines. In anotherclass of this embodiment, each R^(d) is independently selected from thegroup consisting of: —(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₃ alkyl,—(CH₂)_(n)—NR^(b)—(CH₂)_(p)CO₂H, —(CH₂)_(n)—NR^(b)—(CH₂)_(p)CO₂C₁₋₃alkyl, —(CH₂)_(n)—O—(CH₂)_(p)CO₂H, and —(CH₂)_(n)—O—(CH₂)_(p)CO₂C₁₋₃alkyl, wherein any CH₂ in R^(d) is unsubstituted or substituted with oneto two groups independently selected from the group consisting of:halogen, hydroxy, and C₁₋₄ alkyl unsubstituted or substituted with oneto five fluorines. In another class of this embodiment, R^(d) isselected from the group consisting of: —(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₃alkyl, —(CH₂)_(n)—NR^(b)—(CH₂)_(p)CO₂H, and—(CH₂)_(n)—NR^(b)—(CH₂)_(p)CO₂C₁₋₃ alkyl, wherein any CH₂ in R^(d) isunsubstituted or substituted with one to two groups independentlyselected from halogen, hydroxy, and C₁₋₄ alkyl unsubstituted orsubstituted with one to five fluorines. In another class of thisembodiment, R^(d) is selected from the group consisting of:—(CH₂)_(n)CO₂H, and —(CH₂)_(n)—NR^(b)—(CH₂)_(p)CO₂H, wherein any CH₂ inR^(d) is unsubstituted or substituted with one to two groupsindependently selected from halogen, hydroxy, and C₁₋₄ alkylunsubstituted or substituted with one to five fluorines. In anotherclass of this embodiment, R^(d) is selected from the group consistingof: —CH₂CO₂H, and —NH—CH₂CO₂H. In another class of this embodiment,R^(d) is —CH₂CO₂H. In another class of this embodiment, R^(d) is—NH—CH₂CO₂H.

In another embodiment of the present invention, each R^(e) isindependently selected from the group consisting of: hydrogen, and C₁₋₆alkyl, wherein alkyl is unsubstituted or substituted with one to threesubstituents independently selected from the group consisting ofhalogen, cyano, —C₁₋₄ alkoxy, —C₁₋₄ alkylthio, —C₁₋₄ alkylsulfonyl,—CO₂H, and —CO₂C₁₋₄ alkyl. In a class of this embodiment, R^(e) ishydrogen. In another class of this embodiment, R^(e) is C₁₋₆ alkyl,wherein alkyl is unsubstituted or substituted with one to threesubstituents independently selected from the group consisting of:halogen, cyano, —C₁₋₄ alkoxy, alkylthio, —C₁₋₄ alkylsulfonyl, —CO₂H, and—CO₂C₁₋₄ alkyl. In another class of this embodiment, R^(e) is C₁₋₆alkyl.

In another embodiment of the present invention, each R^(g) isindependently selected from the group consisting of: hydrogen, and C₁₋₆alkyl. In a class of this embodiment, R^(g) is hydrogen. In anotherclass of this embodiment, R^(g) is C₁₋₆ alkyl.

In another embodiment of the present invention, g is a single bond or adouble bond. In a class of this embodiment, g is a single bond. Inanother class of this embodiment, g is a double bond.

In another embodiment of the present invention, m is 1, 2, or 3. In aclass of this embodiment, s is 1 or 2. In another class of thisembodiment, m is 2 or 3. In another class of this embodiment, m is 1 or3. In another class of this embodiment, m is 1. In another class of thisembodiment, m is 2. In another class of this embodiment, m is 3.

In another embodiment of the present invention, n is 0, 1, 2 or 3. In aclass of this embodiment, n is 0, 1 or 2. In another class of thisembodiment, n is 0 or 1. In another class of this embodiment, n is 1 or2. In another class of this embodiment, n is 0 or 2. In another class ofthis embodiment, n is 0. In another class of this embodiment, n is 1. Inanother class of this embodiment, n is 2. In another class of thisembodiment, n is 3.

In another embodiment of the present invention, p is 1, 2, or 3. In aclass of this embodiment, p is 1 or 2. In another class of thisembodiment, p is 2 or 3. In another class of this embodiment, p is 1 or3. In another class of this embodiment, p is 1. In another class of thisembodiment, p is 2. In another class of this embodiment, p is 3.

In another embodiment of the present invention, q is 1 or 2. In anotherclass of this embodiment, q is 1. In another class of this embodiment, qis 2.

In another embodiment of the present invention, r is 0, 1, 2 or 3. In aclass of this embodiment, r is 0, 1 or 2. In another class of thisembodiment, r is 0 or 1. In another class of this embodiment, r is 1 or2. In another class of this embodiment, r is 0 or 2. In another class ofthis embodiment, r is 0. In another class of this embodiment, r is 1. Inanother class of this embodiment, r is 2. In another class of thisembodiment, r is 3.

In another embodiment of the present invention, s is 0, 1, 2, 3 or 4. Ina class of this embodiment, s is 0, 1, 2 or 3. In a class of thisembodiment, s is 0, 1 or 2. In another class of this embodiment, s is 0or 1. In another class of this embodiment, s is 1 or 2. In another classof this embodiment, s is 0 or 2. In another class of this embodiment, sis 0. In another class of this embodiment, s is 1. In another class ofthis embodiment, s is 2. In another class of this embodiment, s is 3.

In another embodiment of the present invention, t is 0, 1, 2, 3, 4, 5,6, 7 or 8. In a class of this embodiment, t is 0, 1, 2, 3 or 4. In aclass of this embodiment, t is 0, 1, 2 or 3. In a class of thisembodiment, t is 0, 1 or 2. In another class of this embodiment, t is 0or 1. In another class of this embodiment, t is 1 or 2. In another classof this embodiment, t is 0 or 2. In another class of this embodiment, tis 0. In another class of this embodiment, t is 1. In another class ofthis embodiment, t is 2. In another class of this embodiment, t is 3. Inanother class of this embodiment, t is 4. In another class of thisembodiment, t is 5. In another class of this embodiment, t is 6. Inanother class of this embodiment, t is 7. In another class of thisembodiment, t is 8.

In another embodiment of the present invention, d is 0, 1 or 2. In aclass of this embodiment, d is 0. In another class of this embodiment, dis 1. In another class of this embodiment, d is 2.

In another embodiment of the present invention, e is 0, 1 or 2. In aclass of this embodiment, e is 0. In another class of this embodiment, eis 1. In another class of this embodiment, e is 2.

In another embodiment of the present invention, d is 0, and e is 2. Inanother embodiment of the present invention, d is 1 and e is 1. Inanother embodiment of the present invention, d is 2 and e is 0.

In another embodiment of the present invention, the invention relates tocompounds of structural formula I, wherein:

A is selected from the group consisting of:

B is selected from the group consisting of:

R² is independently selected from the group consisting of: hydrogen,deuterium, halogen, oxo, —C₁₋₆ alkyl, and —OR^(e), wherein alkyl isunsubstituted or substituted with hydroxy or one to three halogens;each R³ is independently selected from the group consisting of:hydrogen, halogen, —C₁₋₆ alkyl, —C₁₋₆ alkenyl, —OC₁₋₆ alkyl, and—(CH₂)_(n)OR^(e), wherein alkyl is unsubstituted or substituted with oneto three substituents selected from: hydroxy, halogen, C₁₋₄ alkyl, C₃₋₆cycloalkyl, C₂₋₅ cycloheteroalkyl, aryl, and heteroaryl wherein alkyl,cycloalkyl, cycloheteroalkyl, aryl and heteroaryl are unsubstituted orsubstituted with one to three substituents selected from: halogen,hydroxy, and C₁₋₄ alkyl unsubstituted or substituted with one to fivefluorines, and wherein any CH₂ in R³ is unsubstituted or substitutedwith one to two groups independently selected from halogen, hydroxy, andC₁₋₄ alkyl unsubstituted or substituted with one to five fluorines;R⁴ is selected from the group consisting of:

s is 0 or 1; and r is 0 or 1; or a pharmaceutically acceptable saltthereof. In a class of this embodiment, each R² is independentlyselected from the group consisting of: R² is independently selected fromthe group consisting of: hydrogen, deuterium, halogen, oxo, —C₁₋₆ alkyl,and —OH; and each R³ is independently selected from the group consistingof: Cl, Br, F, I, —CH₃, —CF₃, —CH₂CH₃, —CH═CH₂, —OCH₃, —OCF₃, —OCH₂CH₃,—OCH₂CH₂F, —O(CH₂)₂CH₃, and —OH.

In another embodiment of the present invention, the invention relates tocompounds of structural formula I, wherein:

A is selected from the group consisting of:

B is selected from the group consisting of:

R⁴ is

R³ is independently selected from the group consisting of: hydrogen,halogen and —OCH₃; and s is 0 or 1; or a pharmaceutically acceptablesalt thereof.

In another embodiment of the present invention, the invention relates tocompounds of structural formula I, wherein:

A is:

B-R⁴ is selected from the group consisting of:

each R³ is independently selected from the group consisting of: Cl, Br,—CH₃, —CF₃, and —OCF₃;

R⁴ is:

ands is 1; or a pharmaceutically acceptable salt thereof.

In another embodiment of the present invention, the invention relates tocompounds of structural formula Ia:

In another embodiment of the present invention, the invention relates tocompounds of structural formula Ib:

In another embodiment of the present invention, the invention relates tocompounds of structural formula Ic:

In another embodiment of the present invention, the invention relates tocompounds of structural formula Id:

In another embodiment of the present invention, the invention relates tocompounds of structural formula Ie:

In another embodiment of the present invention, the invention relates tocompounds of structural formula If:

In another embodiment of the present invention, the invention relates tocompounds of structural formula Ig:

In another embodiment of the present invention, the invention relates tocompounds of structural formula Ih:

In another embodiment of the present invention, the invention relates tocompounds of structural formula Ii:

In another embodiment of the present invention, the invention relates tocompounds of structural formula Ij:

Illustrative, but nonlimiting, examples of compounds of the presentinvention that are useful as inhibitors of SCD are the following:

IC₅₀ Example Structure hSCD-1  1

 12 nM  2

 11 nM  3

 13 nM  4

 41 nM  5

 49 nM  6

 65 nM  7

244 nM  8

708 nM  9

181 nM 10

338 nM 11

 13 nM 12

366 nM 13

 24 nM 14

 12 nM 15

 17 nM 16

 1 nM 17

 1 nM 18

 1 nM 22

 1 nM 28

 1 nM 42

 1 nM 46

 21 nM 54

 62 nM 68

 3 nM 72

 3 nM 75

 1 nM 76

 1 nMand pharmaceutically acceptable salts thereof.

As used herein the following definitions are applicable.

“Alkyl”, as well as other groups having the prefix “alk”, such as alkoxyand alkanoyl, means carbon chains which may be linear or branched, andcombinations thereof, unless the carbon chain is defined otherwise.Examples of alkyl groups include methyl, ethyl, propyl, isopropyl,butyl, sec- and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and thelike. When no number of carbon atoms is specified, C₁₋₆ is intended.

The term “alkenyl” shall mean straight or branched-chain alkenes havingthe specified number of carbon atoms. Examples of alkenyl include vinyl,1-propenyl, 1-butenyl, 2-butenyl, and the like.

The term “alkynyl” refers to straight or branched-chain alkynes havingthe specified number of carbon atoms. Examples of alkynyl includeethynyl, propynyl, butynyl, pentynyl, and the like.

The term “alkoxy” refers to straight or branched chain alkoxides of thenumber of carbon atoms specified (e.g., C₁₋₆ alkoxy), or any numberwithin this range [i.e., methoxy (MeO—), ethoxy, isopropoxy, etc.].

The term “alkylthio” refers to straight or branched chain alkylsulfidesof the number of carbon atoms specified (e.g., C₁₋₆ alkylthio), or anynumber within this range [i.e., methylthio (MeS—), ethylthio,isopropylthio, etc.].

The term “alkylsulfonyl” refers to straight or branched chainalkylsulfones of the number of carbon atoms specified (e.g., C₁₋₆alkylsulfonyl), or any number within this range [i.e., methylsulfonyl(MeSO₂—), ethylsulfonyl, isopropylsulfonyl, etc.].

The term “alkyloxycarbonyl” refers to straight or branched chain estersof a carboxylic acid derivative of the present invention of the numberof carbon atoms specified (e.g., C₁₋₆ alkyloxycarbonyl), or any numberwithin this range [i.e., methyloxycarbonyl (MeOCO—), ethyloxycarbonyl,or butyloxycarbonyl].

“Aryl” means a mono- or polycyclic aromatic ring system containingcarbon ring atoms. The preferred aryls are monocyclic or bicyclic 6-10membered aromatic ring systems. Phenyl and naphthyl are preferred aryls.The most preferred aryl is phenyl.

“Cycloalkyl” means a saturated carbocyclic ring having a specifiednumber of carbon atoms. Examples of cycloalkyl include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and thelike. A cycloalkyl group generally is monocyclic unless statedotherwise. Cycloalkyl groups are saturated unless otherwise defined.

“Cycloheteroalkyl” means nonaromatic, mono- or bicyclic or bridgedsaturated carbocyclic rings, each having from 2 to 14 carbon atoms andcontaining 1, 2, 3, 4 or 5 heteroatoms selected from N, NH, O and S.Examples of cycloheteroalkyl include tetrahydrofuranyl, azetidinyl,perhydroazepinyl, dihydrofuranyl, dioxanyl, oxanyl, morpholinyl,1,4-dithianyl, piperazinyl, piperidinyl, 1,3-dioxolanyl, imidazolidinyl,imidazolinyl, pyrrolinyl, pyrrolidinyl, pyranyl, tetrahydropyranyl,dihydropyranyl, oxathiolanyl, dithiolanyl, 1,3-dithianyl, oxathianyl,thiomorpholinyl, dioxidoisothiazolidinyl, azacycloheptyl,diazobicyclo[3.2.1]-octane, and hexahydroindazolyl. The cycloheteroalkylring may be substituted on the ring carbons and/or the ring nitrogens.In one embodiment of the present invention, cycloheteroalkyl issubstituted or unsubstituted piperazine.

“Heteroaryl” means an aromatic or partially aromatic heterocycle thatcontains at least one ring heteroatom selected from O, S and N.Heteroaryls thus includes heteroaryls fused to other kinds of rings,such as aryls, cycloalkyls and heterocycles that are not aromatic.Examples of heteroaryl groups include: pyrrolyl, isoxazolyl,isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl (in particular,1,3,4-oxadiazol-2-yl and 1,2,4-oxadiazol-3-yl), thiadiazolyl, thiazolyl,imidazolyl, triazolyl, tetrazolyl, furyl, triazinyl, thienyl, pyrimidyl,benzisoxazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl,dihydrobenzofuranyl, indolinyl, pyridazinyl, indazolyl, isoindolyl,dihydrobenzothienyl, indolizinyl, cinnolinyl, phthalazinyl,quinazolinyl, naphthyridinyl, carbazolyl, benzodioxolyl, quinoxalinyl,purinyl, furazanyl, isobenzylfuranyl, benzimidazolyl, benzofuranyl,benzothienyl, quinolyl, indolyl, isoquinolyl, dibenzofuranyl, and thelike. For heterocycloalkyl and heteroaryl groups, rings and ring systemscontaining from 3-15 atoms are included, forming 1-3 rings.

The term “5 membered heteroaryl ring” means an aromatic or partiallyaromatic heterocycle that contains at least one ring heteroatom selectedfrom O, S and N. Examples of 5 membered heteroaryl rings include:pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl,oxadiazolyl (in particular, 1,3,4-oxadiazol-2-yl and1,2,4-oxadiazol-3-yl), thiadiazolyl, thiazolyl, imidazolyl, triazolyl,tetrazolyl, furyl, triazinyl, thienyl, and the like.

“Halogen” refers to fluorine, chlorine, bromine and iodine. Chlorine andfluorine are generally preferred. Fluorine is most preferred when thehalogens are substituted on an alkyl or alkoxy group (e.g. CF₃O andCF₃CH₂O).

The term “compounds of structural formula I” includes the compounds ofstructural formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii, andpharmaceutically acceptable salts thereof.

Compounds of structural formula I may contain one or more asymmetriccenters and can thus occur as racemates and racemic mixtures, singleenantiomers, diastereomeric mixtures and individual diastereomers. Thepresent invention is meant to comprehend all such isomeric forms of thecompounds of structural formula I.

Compounds of structural formula I may be separated into their individualdiastereoisomers by, for example, fractional crystallization from asuitable solvent, for example methanol or ethyl acetate or a mixturethereof, or via chiral chromatography using an optically activestationary phase. Absolute stereochemistry may be determined by X-raycrystallography of crystalline products or crystalline intermediateswhich are derivatized, if necessary, with a reagent containing anasymmetric center of known absolute configuration.

Alternatively, any stereoisomer of a compound of the general structuralformula I may be obtained by stereospecific synthesis using opticallypure starting materials or reagents of known absolute configuration.

If desired, racemic mixtures of the compounds may be separated so thatthe individual enantiomers are isolated. The separation can be carriedout by methods well known in the art, such as the coupling of a racemicmixture of compounds to an enantiomerically pure compound to form adiastereomeric mixture, followed by separation of the individualdiastereomers by standard methods, such as fractional crystallization orchromatography. The coupling reaction is often the formation of saltsusing an enantiomerically pure acid or base. The diasteromericderivatives may then be converted to the pure enantiomers by cleavage ofthe added chiral residue. The racemic mixture of the compounds can alsobe separated directly by chromatographic methods utilizing chiralstationary phases, which methods are well known in the art.

Some of the compounds described herein contain olefinic double bonds,and unless specified otherwise, are meant to include both E and Zgeometric isomers.

Some of the compounds described herein may exist as tautomers, whichhave different points of attachment of hydrogen accompanied by one ormore double bond shifts. For example, a ketone and its enol form areketo-enol tautomers. The individual tautomers as well as mixturesthereof are encompassed with compounds of the present invention.

In the compounds of structural formula I, the atoms may exhibit theirnatural isotopic abundances, or one or more of the atoms may beartificially enriched in a particular isotope having the same atomicnumber, but an atomic mass or mass number different from the atomic massor mass number predominately found in nature. The present invention ismeant to include all suitable isotopic variations of the compounds ofstructural formula I. For example, different isotopic forms of hydrogen(H) include protium (¹H) and deuterium (²H). Protium is the predominanthydrogen isotope found in nature. Enriching for deuterium may affordcertain therapeutic advantages, such as increasing in vivo half-life orreducing dosage requirements, or may provide a compound useful as astandard for characterization of biological samples.Isotopically-enriched compounds within structural formula I, can beprepared without undue experimentation by conventional techniques wellknown to those skilled in the art or by processes analogous to thosedescribed in the Schemes and Examples herein using appropriateisotopically-enriched reagents and/or intermediates.

It will be understood that, as used herein, references to the compoundsof structural formula I are meant to also include the pharmaceuticallyacceptable salts, and also salts that are not pharmaceuticallyacceptable when they are used as precursors to the free compounds ortheir pharmaceutically acceptable salts or in other syntheticmanipulations.

The compounds of the present invention may be administered in the formof a pharmaceutically acceptable salt. The term “pharmaceuticallyacceptable salt” refers to salts prepared from pharmaceuticallyacceptable non-toxic bases or acids including inorganic or organic basesand inorganic or organic acids. Salts of basic compounds encompassedwithin the term “pharmaceutically acceptable salt” refer to non-toxicsalts of the compounds of this invention which are generally prepared byreacting the free base with a suitable organic or inorganic acid.Representative salts of basic compounds of the present inventioninclude, but are not limited to, the following: acetate,benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate,bromide, camsylate, carbonate, chloride, clavulanate, citrate, edetate,edisylate, estolate, esylate, fumarate, gluceptate, gluconate,glutamate, hexylresorcinate, hydrobromide, hydrochloride,hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate,malate, maleate, mandelate, mesylate, methylbromide, methylnitrate,methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammoniumsalt, oleate, oxalate, pamoate (embonate), palmitate, pantothenate,phosphate/diphosphate, polygalacturonate, salicylate, stearate, sulfate,subacetate, succinate, tannate, tartrate, teoclate, tosylate,triethiodide and valerate. Furthermore, where the compounds of theinvention carry an acidic moiety, suitable pharmaceutically acceptablesalts thereof include, but are not limited to, salts derived frominorganic bases including aluminum, ammonium, calcium, copper, ferric,ferrous, lithium, magnesium, manganic, mangamous, potassium, sodium,zinc, and the like. Particularly preferred are the ammonium, calcium,magnesium, potassium, and sodium salts. Salts derived frompharmaceutically acceptable organic non-toxic bases include salts ofprimary, secondary, and tertiary amines, cyclic amines, and basicion-exchange resins, such as arginine, betaine, caffeine, choline,N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine,isopropylamine, lysine, methylglucamine, morpholine, piperazine,piperidine, polyamine resins, procaine, purines, theobromine,triethylamine, trimethylamine, tripropylamine, tromethamine, and thelike.

Also, in the case of a carboxylic acid (—COOH) or alcohol group beingpresent in the compounds of the present invention, pharmaceuticallyacceptable esters of carboxylic acid derivatives, such as methyl, ethyl,or pivaloyloxymethyl, or acyl derivatives of alcohols, such as acetyl,pivaloyl, benzoyl, and aminoacyl, can be employed. Included are thoseesters and acyl groups known in the art for modifying the solubility orhydrolysis characteristics for use as sustained-release or prodrugformulations.

Solvates, in particular hydrates, of the compounds of structural formulaI are included in the present invention as well.

The subject compounds are useful in a method of inhibiting thestearoyl-coenzyme A delta-9 desaturase enzyme (SCD) in a patient such asa mammal in need of such inhibition comprising the administration of aneffective amount of the compound. The compounds of the present inventionare therefore useful to control, prevent, and/or treat conditions anddiseases mediated by high or abnormal SCD enzyme activity.

As defined herein, a condition or disease mediated by high or abnormalSCD enzyme activity is defined as any disease or condition in which theactivity of SCD is elevated and/or where inhibition of SCD can bedemonstrated to bring about symptomatic improvements for the individualso treated. As defined herein, a condition or disease mediated by highor abnormal SCD enzyme activity includes, but is not limited tocardiovascular disease, dyslipidemias, (including but not limiting todisorders of serum levels of triglycerides, hypertriglyceridemia, VLDL,HDL, LDL, cholesterol, and total cholesterol, hypercholesterolemia, aswell as cholesterol disorders), familial combined hyperlipidemia,coronary artery disease, atherosclerosis, heart disease, cerebrovasculardisease (including but not limited to stroke, ischemic stroke, andtransient ischemic attack), peripheral vascular disease, and ischemicretinopathy.

A condition or disease mediated by high or abnormal SCD enzyme activityalso includes metabolic syndrome (including but not limited todyslipidemia, obesity and insulin resistance, hypertension,microalbuminemia, hyperuricaemia, and hypercoagulability), Syndrome X,diabetes, insulin resistance, decreased glucose tolerance,non-insulin-dependent diabetes mellitus, Type II diabetes, Type Idiabetes, diabetic complications, body weight disorders (including butnot limited to obesity, overweight, cacahexia, and anorexia), weightloss, body mass index and leptin-related diseases.

A condition or disease mediated by high or abnormal SCD enzyme activityalso includes fatty liver, hepatic steatosis, hepatitis, non-alcoholichepatitis, non-alcoholic steatohepatitis, alcoholic hepatitis, acutefatty liver, fatty liver of pregnancy, drug-induced hepatitis,erythrohepatic protporphyria, iron overload disorders, hereditaryhemochromatosis, hepatic fibrosis, hepatic cirrhosis, hepatoma andconditions related thereto.

Thus, one aspect of the present invention concerns a method of treatinghyperglycemia, diabetes or insulin resistance in a mammalian patient inneed of such treatment, which comprises administering to said patient aneffective amount of a compound in accordance with structural formula Ior a pharmaceutically salt or solvate thereof.

A second aspect of the present invention concerns a method of treatingnon-insulin dependent diabetes mellitus (Type 2 diabetes) in a mammalianpatient in need of such treatment comprising administering to thepatient an antidiabetic effective amount of a compound in accordancewith structural formula I.

A third aspect of the present invention concerns a method of treatingobesity in a mammalian patient in need of such treatment comprisingadministering to said patient a compound in accordance with structuralformula I in an amount that is effective to treat obesity.

A fourth aspect of the invention concerns a method of treating metabolicsyndrome and its sequelae in a mammalian patient in need of suchtreatment comprising administering to said patient a compound inaccordance with structural formula I in an amount that is effective totreat metabolic syndrome and its sequelae. The sequelae of the metabolicsyndrome include hypertension, elevated blood glucose levels, hightriglycerides, and low levels of HDL cholesterol.

A fifth aspect of the invention concerns a method of treating a lipiddisorder selected from the group consisting of dyslipidemia,hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL andhigh LDL in a mammalian patient in need of such treatment comprisingadministering to said patient a compound in accordance with structuralformula I in an amount that is effective to treat said lipid disorder.

A sixth aspect of the invention concerns a method of treatingatherosclerosis in a mammalian patient in need of such treatmentcomprising administering to said patient a compound in accordance withstructural formula I in an amount effective to treat atherosclerosis.

A seventh aspect of the invention concerns a method of treating cancerin a mammalian patient in need of such treatment comprisingadministering to said patient a compound in accordance with structuralformula I in an amount effective to treat cancer.

A further aspect of the invention concerns a method of treating acondition selected from the group consisting of (1) hyperglycemia, (2)low glucose tolerance, (3) insulin resistance, (4) obesity, (5) lipiddisorders, (6) dyslipidemia, (7) hyperlipidemia, (8)hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL levels,(11) high LDL levels, (12) atherosclerosis and its sequelae, (13)vascular restenosis, (14) pancreatitis, (15) abdominal obesity, (16)neurodegenerative disease, (17) retinopathy, (18) nephropathy, (19)neuropathy, (20) fatty liver disease, (21) polycystic ovary syndrome,(22) sleep-disordered breathing, (23) metabolic syndrome, and (24) otherconditions and disorders where insulin resistance is a component, in amammalian patient in need of such treatment comprising administering tothe patient a compound in accordance with structural formula I in anamount that is effective to treat said condition.

Yet a further aspect of the invention concerns a method of delaying theonset of a condition selected from the group consisting of (1)hyperglycemia, (2) low glucose tolerance, (3) insulin resistance, (4)obesity, (5) lipid disorders, (6) dyslipidemia, (7) hyperlipidemia, (8)hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL levels,(11) high LDL levels, (12) atherosclerosis and its sequelae, (13)vascular restenosis, (14) pancreatitis, (15) abdominal obesity, (16)neurodegenerative disease, (17) retinopathy, (18) nephropathy, (19)neuropathy, (20) fatty liver disease, (21) polycystic ovary syndrome,(22) sleep-disordered breathing, (23) metabolic syndrome, and (24) otherconditions and disorders where insulin resistance is a component, andother conditions and disorders where insulin resistance is a component,in a mammalian patient in need of such treatment comprisingadministering to the patient a compound in accordance with structuralformula I in an amount that is effective to delay the onset of saidcondition.

Yet a further aspect of the invention concerns a method of reducing therisk of developing a condition selected from the group consisting of (1)hyperglycemia, (2) low glucose tolerance, (3) insulin resistance, (4)obesity, (5) lipid disorders, (6) dyslipidemia, (7) hyperlipidemia, (8)hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL levels,(11) high LDL levels, (12) atherosclerosis and its sequelae, (13)vascular restenosis, (14) pancreatitis, (15) abdominal obesity, (16)neurodegenerative disease, (17) retinopathy, (18) nephropathy, (19)neuropathy, (20) fatty liver disease, (21) polycystic ovary syndrome,(22) sleep-disordered breathing, (23) metabolic syndrome, and (24) otherconditions and disorders where insulin resistance is a component, in amammalian patient in need of such treatment comprising administering tothe patient a compound in accordance with structural formula I in anamount that is effective to reduce the risk of developing saidcondition.

In addition to primates, such as humans, a variety of other mammals canbe treated according to the method of the present invention. Forinstance, mammals including, but not limited to, cows, sheep, goats,horses, dogs, cats, guinea pigs, rats or other bovine, ovine, equine,canine, feline, rodent, such as a mouse, species can be treated.However, the method can also be practiced in other species, such asavian species (e.g., chickens).

The present invention is further directed to a method for themanufacture of a medicament for inhibiting stearoyl-coenzyme A delta-9desaturase enzyme activity in humans and animals comprising combining acompound of the present invention with a pharmaceutically acceptablecarrier or diluent. More particularly, the present invention is directedto the use of a compound of structural formula I in the manufacture of amedicament for use in treating a condition selected from the groupconsisting of hyperglycemia, Type 2 diabetes, insulin resistance,obesity, and a lipid disorder in a mammal, wherein the lipid disorder isselected from the group consisting of dyslipidemia, hyperlipidemia,hypertriglyceridemia, hypercholesterolemia, low HDL, and high LDL.

The subject treated in the present methods is generally a mammal,preferably a human being, male or female, in whom inhibition ofstearoyl-coenzyme A delta-9 desaturase enzyme activity is desired. Theterm “therapeutically effective amount” means the amount of the subjectcompound that will elicit the biological or medical response of atissue, system, animal or human that is being sought by the researcher,veterinarian, medical doctor or other clinician.

The term “composition” as used herein is intended to encompass a productcomprising the specified ingredients in the specified amounts, as wellas any product which results, directly or indirectly, from combinationof the specified ingredients in the specified amounts. Such term inrelation to pharmaceutical composition, is intended to encompass aproduct comprising the active ingredient(s) and the inert ingredient(s)that make up the carrier, as well as any product which results, directlyor indirectly, from combination, complexation or aggregation of any twoor more of the ingredients, or from dissociation of one or more of theingredients, or from other types of reactions or interactions of one ormore of the ingredients. Accordingly, the pharmaceutical compositions ofthe present invention encompass any composition made by admixing acompound of the present invention and a pharmaceutically acceptablecarrier. By “pharmaceutically acceptable” it is meant the carrier,diluent or excipient must be compatible with the other ingredients ofthe formulation and not deleterious to the recipient thereof.

The terms “administration of” and or “administering a” compound shouldbe understood to mean providing a compound of the invention or a prodrugof a compound of the invention to the individual in need of treatment.

The utility of the compounds in accordance with the present invention asinhibitors of stearoyl-coenzyme A delta-9 desaturase (SCD) enzymeactivity may be demonstrated by the following microsomal and whole-cellbased assays:

I. SCD Enzyme Activity Assay:

The potency of compounds of formula I against the stearoyl-CoAdesaturase was determined by measuring the conversion of radiolabeledstearoyl-CoA to oleoyl-CoA using rat liver microsome or human SCD1following previously published procedures with some modifications(Joshi, et al., J. Lipid Res., 18: 32-36 (1977); Talamo, et al., Anal.Biochem, 29: 300-304 (1969)). Liver microsome was prepared from maleWistar or Sprague Dawley rats on a high carbohydrate diet for 3 days(LabDiet #5803, Purina). The livers were homogenized (1:10 w/v) in abuffer containing 250 mM sucrose, 1 mM EDTA, 5 mM DTT and 50 mM Tris-HCl(pH 7.5). After a 100,000×g centrifugation for 60 min, the livermicrosome pellet was suspended in a buffer containing 100 mM sodiumphosphate, 20% glycerol, 2 mM DTT, and stored at −78° C. Human SCD1desaturase system was reconstituted using human SCD1 from abaculovirus/SD expression system, cytochrome B5 and cytochrome B5reductase. Typically, test compound in 2 μL DMSO was incubated for 15 mMat room temperature with 180 μL of the SCD enzyme in a buffer containing100 mM Tris-HCl (pH 7.5), ATP (5 mM), Coenzyme-A (0.1 mM), Triton X-100(0.5 mM) and NADH (2 mM). The reaction was initiated by the addition of20 μL of [³H]-stearoyl-CoA (final concentration=2 μM, radioactivityconcentration=1 μCi/mL). After 10 mM, the reaction mixture (80 μL) wasmixed with a calcium chloride/charcoal aqueous suspension (100 μLcharcoal (10% w/v) plus 25 μL CaCl₂ (2N). After centrifugation toprecipitate the radioactive fatty acid species, tritiated water releasedfrom 9,10-[³H]-stearoyl-CoA by the SCD enzyme was quantified on ascintillation counter.

II. Whole Cell-Based SCD (Delta-9), Delta-5 and Delta-6 DesaturaseAssays:

Human HepG2 cells were grown on 24-well plates in MEM media (Gibcocat#11095-072) supplemented with 10% heat-inactivated fetal bovine serumat 37° C. under 5% CO₂ in a humidified incubator. Test compounddissolved in the media was incubated with the subconfluent cells for 15mM at 37° C. [1-¹⁴C]-stearic acid was added to each well to a finalconcentration of 0.05 μCi/mL to detect SCD-catalyzed [¹⁴C]-oleic acidformation. 0.05 μCi/mL of [1-¹⁴C]-eicosatrienoic acid or[1-¹⁴C]-linolenic acid plus 10 μM of 2-amino-N-(3-chlorophenyl)benzamide(a delta-5 desaturase inhibitor) was used to index the delta-5 anddelta-6 desaturase activities, respectively. After 4 h incubation at 37°C., the culture media was removed and the labeled cells were washed withPBS (3×1 mL) at room temperature. The labeled cellular lipids werehydrolyzed under nitrogen at 65° C. for 1 h using 400 pt of 2N sodiumhydroxide plus 50 μl of L-α-phosphatidylcholine (2 mg/mL in isopropanol,Sigma #P-3556). After acidification with phosphoric acid (60 μL), theradioactive species were extracted with 300 μL of acetonitrile andquantified on a HPLC that was equipped with a C-18 reverse phase columnand a Packard Flow Scintillation Analyzer. The levels of [¹⁴C]-oleicacid over [¹⁴C]-stearic acid, [¹⁴C]-arachidonic acid over[¹⁴C]-eicosatrienoic acid, and [¹⁴C]-eicosatetraenoic acid (8, 11, 14,17) over [¹⁴C]-linolenic acid were used as the corresponding activityindices of SCD, delta-5 and delta-6 desaturase, respectively.

The compounds of the present invention, including the compounds ofExamples 1 to 81, exhibit an SCD inhibition constant IC₅₀ of less than 1μM. Preferred compounds of the present invention were found to exhibitan SCD inhibition constant IC₅₀ of less than 0.1 μM.

In Vivo Efficacy of Compounds of the Present Invention:

The in vivo efficacy of compounds of formula I was determined byfollowing the conversion of [1-¹⁴C]-stearic acid to [1-¹⁴C]oleic acid inanimals as exemplified below. Mice were dosed with a compound of formulaI and one hour later the radioactive tracer, [1-¹⁴C]-stearic acid, wasdosed at 20 μCi/kg IV. At 3 h post dosing of the compound, the liver washarvested and then hydrolyzed in 10 N sodium hydroxide for 24 h at 80°C., to obtain the total liver fatty acid pool. After phosphoric acidacidification of the extract, the amount of [1-¹⁴C]-stearic acid and[1-¹⁴C]-oleic acid was quantified on a HPLC that was equipped with aC-18 reverse phase column and a Packard Flow Scintillation Analyzer.

The subject compounds are further useful in a method for the preventionor treatment of the aforementioned diseases, disorders and conditions incombination with other agents.

The compounds of the present invention may be used in combination withone or more other drugs in the treatment, prevention, suppression oramelioration of diseases or conditions for which compounds of Formula Ior the other drugs may have utility, where the combination of the drugstogether are safer or more effective than either drug alone. Such otherdrug(s) may be administered, by a route and in an amount commonly usedtherefor, contemporaneously or sequentially with a compound of FormulaI. When a compound of Formula I is used contemporaneously with one ormore other drugs, a pharmaceutical composition in unit dosage formcontaining such other drugs and the compound of Formula I is preferred.However, the combination therapy may also include therapies in which thecompound of formula I and one or more other drugs are administered ondifferent overlapping schedules. It is also contemplated that when usedin combination with one or more other active ingredients, the compoundsof the present invention and the other active ingredients may be used inlower doses than when each is used singly. Accordingly, thepharmaceutical compositions of the present invention include those thatcontain one or more other active ingredients, in addition to a compoundof Formula I.

The compounds of the present invention may be used in combination withone or more other drugs in the treatment, prevention, suppression oramelioration of diseases or conditions for which compounds of Formula Ior the other drugs may have utility, where the combination of the drugstogether are safer or more effective than either drug alone. Such otherdrug(s) may be administered, by a route and in an amount commonly usedtherefor, contemporaneously or sequentially with a compound of FormulaI. When a compound of Formula I is used contemporaneously with one ormore other drugs, a pharmaceutical composition in unit dosage formcontaining such other drugs and the compound of Formula I is preferred.However, the combination therapy may also include therapies in which thecompound of formula I and one or more other drugs are administered ondifferent overlapping schedules. It is also contemplated that when usedin combination with one or more other active ingredients, the compoundsof the present invention and the other active ingredients may be used inlower doses than when each is used singly. Accordingly, thepharmaceutical compositions of the present invention include those thatcontain one or more other active ingredients, in addition to a compoundof Formula I.

Examples of other active ingredients that may be administered incombination with a compound of formula I, and either administeredseparately or in the same pharmaceutical composition, include, but arenot limited to:

(a) dipeptidyl peptidase-IV (DPP-4) inhibitors;

(b) insulin sensitizers including (i) PPARγ agonists, such as theglitazones (e.g. troglitazone, pioglitazone, englitazone, MCC-555,rosiglitazone, balaglitazone, and the like) and other PPAR ligands,including PPARα/γ dual agonists, such as KRP-297, muraglitazar,naveglitazar, Galida, TAK-559, PPARα agonists, such as fenofibric acidderivatives (gemfibrozil, clofibrate, fenofibrate and bezafibrate), andselective PPARγ modulators (SPPARγM's), such as disclosed in WO02/060388, WO 02/08188, WO 2004/019869, WO 2004/020409, WO 2004/020408,and WO 2004/066963; (ii) biguanides such as metformin and phenformin,and (iii) protein tyrosine phosphatase-1B (PTP-1B) inhibitors;

(c) insulin or insulin mimetics;

(d) sulfonylureas and other insulin secretagogues, such as tolbutamide,glyburide, glipizide, glimepiride, and meglitinides, such as nateglinideand repaglinide;

(e) α-glucosidase inhibitors (such as acarbose and miglitol);

(f) glucagon receptor antagonists, such as those disclosed in WO98/04528, WO 99/01423, WO 00/39088, and WO 00/69810;

(g) GLP-1, GLP-1 analogues or mimetics, and GLP-1 receptor agonists,such as exendin-4 (exenatide), liraglutide (N,N-2211), CJC-1131,LY-307161, and those disclosed in WO 00/42026 and WO 00/59887;

(h) GIP and GIP mimetics, such as those disclosed in WO 00/58360, andGIP receptor agonists;

(i) PACAP, PACAP mimetics, and PACAP receptor agonists such as thosedisclosed in WO 01/23420;

(j) cholesterol lowering agents such as (i) HMG-CoA reductase inhibitors(lovastatin, simvastatin, pravastatin, cerivastatin, fluvastatin,atorvastatin, itavastatin, and rosuvastatin, and other statins), (ii)sequestrants (cholestyramine, colestipol, and dialkylaminoalkylderivatives of a cross-linked dextran), (iii) nicotinyl alcohol,nicotinic acid or a salt thereof, (iv) PPARα agonists such as fenofibricacid derivatives (gemfibrozil, clofibrate, fenofibrate and bezafibrate),(v) PPARα/γ dual agonists, such as naveglitazar and muraglitazar, (vi)inhibitors of cholesterol absorption, such as beta-sitosterol andezetimibe, (vii) acyl CoA:cholesterol acyltransferase inhibitors, suchas avasimibe, and (viii) antioxidants, such as probucol;

(k) PPARδ agonists, such as those disclosed in WO 97/28149;

(l) antiobesity compounds, such as fenfluramine, dexfenfluramine,phentermine, sibutramine, orlistat, neuropeptide Y₁ or Y₅ antagonists,CB1 receptor inverse agonists and antagonists, β₃ adrenergic receptoragonists, melanocortin-receptor agonists, in particular melanocortin-4receptor agonists, ghrelin antagonists, bombesin receptor agonists (suchas bombesin receptor subtype-3 agonists), and melanin-concentratinghormone (MCH) receptor antagonists;

(m) ileal bile acid transporter inhibitors;

(n) agents intended for use in inflammatory conditions such as aspirin,non-steroidal anti-inflammatory drugs (NSAIDs), glucocorticoids,azulfidine, and selective cyclooxygenase-2 (COX-2) inhibitors;

(o) antihypertensive agents, such as ACE inhibitors (enalapril,lisinopril, captopril, quinapril, tandolapril), A-II receptor blockers(losartan, candesartan, irbesartan, valsartan, telmisartan, andeprosartan), beta blockers and calcium channel blockers;

(p) glucokinase activators (GKAs), such as those disclosed in WO03/015774; WO 04/076420; and WO 04/081001;

(q) inhibitors of 11β-hydroxysteroid dehydrogenase type 1, such as thosedisclosed in U.S. Pat. No. 6,730,690; WO 03/104207; and WO 04/058741;

(r) inhibitors of cholesteryl ester transfer protein (CETP), such astorcetrapib;

(s) inhibitors of fructose 1,6-bisphosphatase, such as those disclosedin U.S. Pat. Nos. 6,054,587; 6,110,903; 6,284,748; 6,399,782; and6,489,476;

(t) acetyl CoA carboxylase-1 and/or -2 inhibitors;

(u) AMPK activators; and

(v) agonists of GPR-119.

Dipeptidyl peptidase-IV inhibitors that can be combined with compoundsof structural formula I include those disclosed in U.S. Pat. No.6,699,871; WO 02/076450 (3 Oct. 2002); WO 03/004498 (16 Jan. 2003); WO03/004496 (16 Jan. 2003); EP 1 258 476 (20 Nov. 2002); WO 02/083128 (24Oct. 2002); WO 02/062764 (15 Aug. 2002); WO 03/000250 (3 Jan. 2003); WO03/002530 (9 Jan. 2003); WO 03/002531 (9 Jan. 2003); WO 03/002553 (9Jan. 2003); WO 03/002593 (9 Jan. 2003); WO 03/000180 (3 Jan. 2003); WO03/082817 (9 Oct. 2003); WO 03/000181 (3 Jan. 2003); WO 04/007468 (22Jan. 2004); WO 04/032836 (24 Apr. 2004); WO 04/037169 (6 May 2004); andWO 04/043940 (27 May 2004). Specific DPP-IV inhibitor compounds includesitagliptin (MK-0431); vildagliptin (LAF 237); denagliptin; P93/01;saxagliptin (BMS 477118); RO0730699; MP513; SYR-322: ABT-279; PHX1149;GRC-8200; and TS021.

Antiobesity compounds that can be combined with compounds of structuralformula I include fenfluramine, dexfenfluramine, phentermine,sibutramine, orlistat, neuropeptide Y₁ or Y₅ antagonists, cannabinoidCB1 receptor antagonists or inverse agonists, melanocortin receptoragonists, in particular, melanocortin-4 receptor agonists, ghrelinantagonists, bombesin receptor agonists, and melanin-concentratinghormone (MCH) receptor antagonists. For a review of anti-obesitycompounds that can be combined with compounds of structural formula I,see S. Chaki et al., “Recent advances in feeding suppressing agents:potential therapeutic strategy for the treatment of obesity,” ExpertOpin. Ther. Patents, 11: 1677-1692 (2001); D. Spanswick and K. Lee,“Emerging antiobesity drugs,” Expert Opin. Emerging Drugs, 8: 217-237(2003); and J. A. Fernandez-Lopez, et al., “Pharmacological Approachesfor the Treatment of Obesity,” Drugs, 62: 915-944 (2002).

Neuropeptide Y5 antagonists that can be combined with compounds ofstructural formula I include those disclosed in U.S. Pat. No. 6,335,345(1 Jan. 2002) and WO 01/14376 (1 Mar. 2001); and specific compoundsidentified as GW 59884A; GW 569180A; LY366377; and CGP-71683A.

Cannabinoid CB1 receptor antagonists that can be combined with compoundsof formula I include those disclosed in PCT Publication WO 03/007887;U.S. Pat. No. 5,624,941, such as rimonabant; PCT Publication WO02/076949, such as SLV-319; U.S. Pat. No. 6,028,084; PCT Publication WO98/41519; PCT Publication WO 00/10968; PCT Publication WO 99/02499; U.S.Pat. No. 5,532,237; U.S. Pat. No. 5,292,736; PCT Publication WO03/086288; PCT Publication WO 03/087037; PCT Publication WO 04/048317;PCT Publication WO 03/007887; PCT Publication WO 03/063781; PCTPublication WO 03/075660; PCT Publication WO 03/077847; PCT PublicationWO 03/082190; PCT Publication WO 03/082191; PCT Publication WO03/087037; PCT Publication WO 03/086288; PCT Publication WO 04/012671;PCT Publication WO 04/029204; PCT Publication WO 04/040040; PCTPublication WO 01/64632; PCT Publication WO 01/64633; and PCTPublication WO 01/64634.

Melanocortin-4 receptor (MC4R) agonists useful in the present inventioninclude, but are not limited to, those disclosed in U.S. Pat. No.6,294,534, U.S. Pat. Nos. 6,350,760, 6,376,509, 6,410,548, 6,458,790,U.S. Pat. No. 6,472,398, U.S. Pat. No. 5,837,521, U.S. Pat. No.6,699,873, which are hereby incorporated by reference in their entirety;in US Patent Application Publication Nos. US 2002/0004512,US2002/0019523, US2002/0137664, US2003/0236262, US2003/0225060,US2003/0092732, US2003/109556, US 2002/0177151, US 2002/187932, US2003/0113263, which are hereby incorporated by reference in theirentirety; and in WO 99/64002, WO 00/74679, WO 02/15909, WO 01/70708, WO01/70337, WO 01/91752, WO 02/068387, WO 02/068388, WO 02/067869, WO03/007949, WO 2004/024720, WO 2004/089307, WO 2004/078716, WO2004/078717, WO 2004/037797, WO 01/58891, WO 02/070511, WO 02/079146, WO03/009847, WO 03/057671, WO 03/068738, WO 03/092690, WO 02/059095, WO02/059107, WO 02/059108, WO 02/059117, WO 02/085925, WO 03/004480, WO03/009850, WO 03/013571, WO 03/031410, WO 03/053927, WO 03/061660, WO03/066597, WO 03/094918, WO 03/099818, WO 04/037797, WO 04/048345, WO02/018327, WO 02/080896, WO 02/081443, WO 03/066587, WO 03/066597, WO03/099818, WO 02/062766, WO 03/000663, WO 03/000666, WO 03/003977, WO03/040107, WO 03/040117, WO 03/040118, WO 03/013509, WO 03/057671, WO02/079753, WO 02/092566, WO 03/-093234, WO 03/095474, and WO 03/104761.

One particular aspect of combination therapy concerns a method oftreating a condition selected from the group consisting ofhypercholesterolemia, atherosclerosis, low HDL levels, high LDL levels,hyperlipidemia, hypertriglyceridemia, and dyslipidemia, in a mammalianpatient in need of such treatment comprising administering to thepatient a therapeutically effective amount of a compound of structuralformula I and an HMG-CoA reductase inhibitor.

More particularly, this aspect of combination therapy concerns a methodof treating a condition selected from the group consisting ofhypercholesterolemia, atherosclerosis, low HDL levels, high LDL levels,hyperlipidemia, hypertriglyceridemia and dyslipidemia in a mammalianpatient in need of such treatment wherein the HMG-CoA reductaseinhibitor is a statin selected from the group consisting of lovastatin,simvastatin, pravastatin, cerivastatin, fluvastatin, atorvastatin, androsuvastatin.

In another aspect of the invention, a method of reducing the risk ofdeveloping a condition selected from the group consisting ofhypercholesterolemia, atherosclerosis, low HDL levels, high LDL levels,hyperlipidemia, hypertriglyceridemia and dyslipidemia, and the sequelaeof such conditions is disclosed comprising administering to a mammalianpatient in need of such treatment a therapeutically effective amount ofa compound of structural formula I and an HMG-CoA reductase inhibitor.

In another aspect of the invention, a method for delaying the onset orreducing the risk of developing atherosclerosis in a human patient inneed of such treatment is disclosed comprising administering to saidpatient an effective amount of a compound of structural formula I and anHMG-CoA reductase inhibitor.

More particularly, a method for delaying the onset or reducing the riskof developing atherosclerosis in a human patient in need of suchtreatment is disclosed, wherein the HMG-CoA reductase inhibitor is astatin selected from the group consisting of: lovastatin, simvastatin,pravastatin, cerivastatin, fluvastatin, atorvastatin, and rosuvastatin.

In another aspect of the invention, a method for delaying the onset orreducing the risk of developing atherosclerosis in a human patient inneed of such treatment is disclosed, wherein the HMG-Co A reductaseinhibitor is a statin and further comprising administering a cholesterolabsorption inhibitor.

More particularly, in another aspect of the invention, a method fordelaying the onset or reducing the risk of developing atherosclerosis ina human patient in need of such treatment is disclosed, wherein theHMG-Co A reductase inhibitor is a statin and the cholesterol absorptioninhibitor is ezetimibe.

In another aspect of the invention, a pharmaceutical composition isdisclosed which comprises:

(1) a compound of structural formula I;(2) a compound selected from the group consisting of:

-   -   (a) dipeptidyl peptidase IV (DPP-IV) inhibitors;    -   (b) insulin sensitizers including (i) PPARγ agonists, such as        the glitazones (e.g. troglitazone, pioglitazone, englitazone,        MCC-555, rosiglitazone, balaglitazone, and the like) and other        PPAR ligands, including PPARα/γ dual agonists, such as KRP-297,        muraglitazar, naveglitazar, Galida, TAK-559, PPARα agonists,        such as fenofibric acid derivatives (gemfibrozil, clofibrate,        fenofibrate and bezafibrate), and selective PPARγ modulators        (SPPARγM's), such as disclosed in WO 02/060388, WO 02/08188, WO        2004/019869, WO 2004/020409, WO 2004/020408, and WO        2004/066963; (ii) biguanides such as metformin and phenformin,        and (iii) protein tyrosine phosphatase-1B (PTP-1B) inhibitors;    -   (c) insulin or insulin mimetics;    -   (d) sulfonylureas and other insulin secretagogues, such as        tolbutamide, glyburide, glipizide, glimepiride, and        meglitinides, such as nateglinide and repaglinide;    -   (e) α-glucosidase inhibitors (such as acarbose and miglitol);    -   (f) glucagon receptor antagonists, such as those disclosed in WO        98/04528, WO 99/01423, WO 00/39088, and WO 00/69810;    -   (g) GLP-1, GLP-1 analogues or mimetics, and GLP-1 receptor        agonists, such as exendin-4 (exenatide), liraglutide (N,N-2211),        CJC-1131, LY-307161, and those disclosed in WO 00/42026 and WO        00/59887;    -   (h) GIP and GIP mimetics, such as those disclosed in WO        00/58360, and GIP receptor agonists;    -   (i) PACAP, PACAP mimetics, and PACAP receptor agonists such as        those disclosed in WO 01/23420;    -   (j) cholesterol lowering agents such as (i) HMG-CoA reductase        inhibitors (lovastatin, simvastatin, pravastatin, cerivastatin,        fluvastatin, atorvastatin, itavastatin, and rosuvastatin, and        other statins), (ii) sequestrants (cholestyramine, colestipol,        and dialkylaminoalkyl derivatives of a cross-linked        dextran), (iii) nicotinyl alcohol, nicotinic acid or a salt        thereof, (iv) PPARα agonists such as fenofibric acid derivatives        (gemfibrozil, clofibrate, fenofibrate and bezafibrate), (v)        PPARα/γ dual agonists, such as naveglitazar and        muraglitazar, (vi) inhibitors of cholesterol absorption, such as        beta-sitosterol and ezetimibe, (vii) acyl CoA:cholesterol        acyltransferase inhibitors, such as avasimibe, and (viii)        antioxidants, such as probucol;    -   (k) PPARδ agonists, such as those disclosed in WO 97/28149;    -   (l) antiobesity compounds, such as fenfluramine,        dexfenfluramine, phentermine, sibutramine, orlistat,        neuropeptide Y₁ or Y₅ antagonists, CB1 receptor inverse agonists        and antagonists, β₃ adrenergic receptor agonists,        melanocortin-receptor agonists, in particular melanocortin-4        receptor agonists, ghrelin antagonists, bombesin receptor        agonists (such as bombesin receptor subtype-3 agonists), and        melanin-concentrating hormone (MCH) receptor antagonists;    -   (m) ileal bile acid transporter inhibitors;    -   (n) agents intended for use in inflammatory conditions such as        aspirin, non-steroidal anti-inflammatory drugs (NSAIDs),        glucocorticoids, azulfidine, and selective cyclooxygenase-2        (COX-2) inhibitors;    -   (o) antihypertensive agents, such as ACE inhibitors (enalapril,        lisinopril, captopril, quinapril, tandolapril), A-II receptor        blockers (losartan, candesartan, irbesartan, valsartan,        telmisartan, and eprosartan), beta blockers and calcium channel        blockers;    -   (p) glucokinase activators (GKAs), such as those disclosed in WO        03/015774; WO 04/076420; and WO 04/081001;    -   (q) inhibitors of 11β-hydroxysteroid dehydrogenase type 1, such        as those disclosed in U.S. Pat. No. 6,730,690; WO 03/104207; and        WO 04/058741;    -   (r) inhibitors of cholesteryl ester transfer protein (CETP),        such as torcetrapib;    -   (s) inhibitors of fructose 1,6-bisphosphatase, such as those        disclosed in U.S. Pat. Nos. 6,054,587; 6,110,903; 6,284,748;        6,399,782; and 6,489,476;    -   (t) acetyl CoA carboxylase-1 and/or -2 inhibitors;    -   (u) AMPK activators; and    -   (v) agonists of GPR 119; and        (3) a pharmaceutically acceptable carrier.

When a compound of the present invention is used contemporaneously withone or more other drugs, a pharmaceutical composition containing suchother drugs in addition to the compound of the present invention ispreferred. Accordingly, the pharmaceutical compositions of the presentinvention include those that also contain one or more other activeingredients, in addition to a compound of the present invention.

The weight ratio of the compound of the present invention to the secondactive ingredient may be varied and will depend upon the effective doseof each ingredient. Generally, an effective dose of each will be used.Thus, for example, when a compound of the present invention is combinedwith another agent, the weight ratio of the compound of the presentinvention to the other agent will generally range from about 1000:1 toabout 1:1000, preferably about 200:1 to about 1:200. Combinations of acompound of the present invention and other active ingredients willgenerally also be within the aforementioned range, but in each case, aneffective dose of each active ingredient should be used.

In such combinations the compound of the present invention and otheractive agents may be administered separately or in conjunction. Inaddition, the administration of one element may be prior to, concurrentto, or subsequent to the administration of other agent(s).

The compounds of the present invention may be administered by oral,parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV,intracisternal injection or infusion, subcutaneous injection, orimplant), by inhalation spray, nasal, vaginal, rectal, sublingual, ortopical routes of administration and may be formulated, alone ortogether, in suitable dosage unit formulations containing conventionalnon-toxic pharmaceutically acceptable carriers, adjuvants and vehiclesappropriate for each route of administration. In addition to thetreatment of warm-blooded animals such as mice, rats, horses, cattle,sheep, dogs, cats, monkeys, etc., the compounds of the invention areeffective for use in humans.

The pharmaceutical compositions for the administration of the compoundsof this invention may conveniently be presented in dosage unit form andmay be prepared by any of the methods well known in the art of pharmacy.All methods include the step of bringing the active ingredient intoassociation with the carrier which constitutes one or more accessoryingredients. In general, the pharmaceutical compositions are prepared byuniformly and intimately bringing the active ingredient into associationwith a liquid carrier or a finely divided solid carrier or both, andthen, if necessary, shaping the product into the desired formulation. Inthe pharmaceutical composition the active object compound is included inan amount sufficient to produce the desired effect upon the process orcondition of diseases. As used herein, the term “composition” isintended to encompass a product comprising the specified ingredients inthe specified amounts, as well as any product which results, directly orindirectly, from combination of the specified ingredients in thespecified amounts.

The pharmaceutical compositions containing the active ingredient may bein a form suitable for oral use, for example, as tablets, troches,lozenges, aqueous or oily suspensions, dispersible powders or granules,emulsions, hard or soft capsules, or syrups or elixirs. Compositionsintended for oral use may be prepared according to any method known tothe art for the manufacture of pharmaceutical compositions and suchcompositions may contain one or more agents selected from the groupconsisting of sweetening agents, flavoring agents, coloring agents andpreserving agents in order to provide pharmaceutically elegant andpalatable preparations. Tablets contain the active ingredient inadmixture with non-toxic pharmaceutically acceptable excipients whichare suitable for the manufacture of tablets. These excipients may be forexample, inert diluents, such as calcium carbonate, sodium carbonate,lactose, calcium phosphate or sodium phosphate; granulating anddisintegrating agents, for example, corn starch, or alginic acid;binding agents, for example starch, gelatin or acacia, and lubricatingagents, for example magnesium stearate, stearic acid or talc. Thetablets may be uncoated or they may be coated by known techniques todelay disintegration and absorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. For example, atime delay material such as glyceryl monostearate or glyceryl distearatemay be employed. They may also be coated by the techniques described inthe U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotictherapeutic tablets for control release.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose,sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally-acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The compounds of the present invention may also be administered in theform of suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols.

For topical use, creams, ointments, jellies, solutions or suspensions,etc., containing the compounds of the present invention are employed.(For purposes of this application, topical application shall includemouthwashes and gargles.)

The pharmaceutical composition and method of the present invention mayfurther comprise other therapeutically active compounds as noted hereinwhich are usually applied in the treatment of the above mentionedpathological conditions.

In the treatment or prevention of conditions which require inhibition ofstearoyl-CoA delta-9 desaturase enzyme activity an appropriate dosagelevel will generally be about 0.01 to 500 mg per kg patient body weightper day which can be administered in single or multiple doses.Preferably, the dosage level will be about 0.1 to about 250 mg/kg perday; more preferably about 0.5 to about 100 mg/kg per day. A suitabledosage level may be about 0.01 to 250 mg/kg per day, about 0.05 to 100mg/kg per day, or about 0.1 to 50 mg/kg per day. Within this range thedosage may be 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg/kg per day. For oraladministration, the compositions are preferably provided in the form oftablets containing 1.0 to 1000 mg of the active ingredient, particularly1.0, 5.0, 10.0, 15.0. 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0,250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 mg ofthe active ingredient for the symptomatic adjustment of the dosage tothe patient to be treated. The compounds may be administered on aregimen of 1 to 4 times per day, preferably once or twice per day.

When treating or preventing diabetes mellitus and/or hyperglycemia orhypertriglyceridemia or other diseases for which compounds of thepresent invention are indicated, generally satisfactory results areobtained when the compounds of the present invention are administered ata daily dosage of from about 0.1 mg to about 100 mg per kilogram ofanimal body weight, preferably given as a single daily dose or individed doses two to six times a day, or in sustained release form. Formost large mammals, the total daily dosage is from about 1.0 mg to about1000 mg, preferably from about 1 mg to about 50 mg. In the case of a 70kg adult human, the total daily dose will generally be from about 7 mgto about 350 mg. This dosage regimen may be adjusted to provide theoptimal therapeutic response.

It will be understood, however, that the specific dose level andfrequency of dosage for any particular patient may be varied and willdepend upon a variety of factors including the activity of the specificcompound employed, the metabolic stability and length of action of thatcompound, the age, body weight, general health, sex, diet, mode and timeof administration, rate of excretion, drug combination, the severity ofthe particular condition, and the host undergoing therapy.

Preparation of Compounds of the Invention:

The compounds of structural formula I can be prepared according to theprocedures of the following Schemes and Examples, using appropriatematerials and are further exemplified by the following specific example.The compound illustrated in the example is not, however, to be construedas forming the only genus that is considered as the invention. TheExample further illustrates details for the preparation of the compoundsof the present invention. Those skilled in the art will readilyunderstand that known variations of the conditions and processes of thefollowing preparative procedures can be used to prepare these compounds.All temperatures are degrees Celsius unless otherwise noted. Massspectra (MS) were measured by electrospray ion-mass spectroscopy (ESMS).

List of Abbreviations: ACN is acetonitrile; Ac₂O is acetic anhydride;AcOH is acetic acid; aq is aqueous; Boc is tert-butyloxycarbonyl; n-BuLiis n-butyl lithium; t-BuOH is tert-butanol; t-BuLi is tert-butyllithium; t-BuONO is tert-butyl nitrite; CAN is ceric ammonium nitrate;Celite™ is diatomaceous earth; CuSO₄ is copper sulfate; DAST is(diethylamino)sulfur trifluoride; DBU is1,8-diazabicyclo-[5.4.0]undec-7-ene; DCM is dichloromethane; DEAD:diethyl azodicarboxylate; DIPEA or DIEA is N,N-diisopropyl ethyl amine(Hunig's base); DME is 1,2-dimethoxyethane; DMAP is 4-dimethyl aminopyridine; DMF is N,N-dimethylformamide; DMSO is dimethyl sulfoxide; DPPAis diphenyl phosphoryl azide; dppf is1,1′-bis(diphenylphosphino)ferrocene; EA is ethyl acetate; equiv isequivalent(s); ESI is electrospray ionization; Et₃N is triethylamine;Et₃SiH is triethylsilane; EtOAc is ethyl acetate; EtOH is ethyl alcohol;Et₂O is diethyl ether; g is gram(s); h is hour(s); HATU is(2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate); HCl is hydrochloric acid; HMPA ishexamethylphosphoramide; in vacuo is rotary evaporation under diminishedpressure; i-PrOH or IPA is isopropanol; K₂CO₃ is potassium carbonate; LCis liquid chromatography; LC/MS is liquid chromatography/massspectroscopy; L is liter(s); LiHMDS is lithium hexamethyldisilazide; mland mL is milliliter; M is molar; mmol is millimole(s); MeOH is methylalcohol; MgSO₄ is magnesium sulfate; min is minute(s); MS is massspectrum; MOMCl is chloromethyl methyl ether; MTBE is methyl tert-butylether; NaOH is sodium hydroxide; NaN₃ is sodium azide; NaOAC is sodiumacetate; NMP is N-methyl-2-pyrrolidinone; NMR is nuclear magneticresonance spectroscopy; PE is petroleum ether; Ph is phenyl; PPh₃ istriphenyl phosphine; sat. and sat is saturated; SiO₂ is silicon dioxide;rt and RT is room temperature; TEA is triethyl amine; TFA istrifluoroacetic acid; TFAA is trifluoroacetic anhydride; THF istetrahydrofuran; TMP is 2,2,6,6-tetramethylpiperidine; and wt % isweight percent.

Method A

The spiro moieties can be prepared according to the procedures describedby L. Yang., et. al., Bioorg. Med. Chem. Lett., 8, 107-112 (1998). Hereis an illustration with A-5. An appropriately substituted2′-hydroxyacetophenone A-1 is reacted with an appropriately substitutedcyclic ketone intermediate A-2 in the presence of a base, such aspyrrolidine, in a solvent, such as methanol, to give thespiro-intermediate A-3.

The carbonyl of intermediate A-3 is then reduced in a 2-step sequencevia alcohol A-4 to give the spiro-cyclic amine intermediate A-5 forfurther coupling reaction. The spiro intermediate A-5 is either isolatedas a free base or a salt with an acid such as HCl or TFA. For R³═OH inA-4, it can be further react with an alkyl or benzyl group to providethe corresponding alkylated analog.

Method B

An appropriately substituted spiro intermediate B-1, prepared accordingthe Method A, is reacted with an appropriately halo-substituted (X′═Cl,Br) heteroaryl B-2, wherein heteroaryl ring B is as previously defined,and Y′ is a functional group such as halogen (Cl, Br, I), ester, amide,nitrile or heterocycle which is suitable for the transformation tosubstituent R⁴ as previously defined. The functional group Y′ is thenconverted by typical standard transformations to substituent R⁴ to givethe desired moiety for final product B-3. For R³═OH in B-1, it can befurther transformed to the corresponding alkylated analog after couplingreaction with B-2 at an appropriate step. Other spiro moieties can beused to couple with B-2 to obtain the corresponding analogs.

Intermediate 1

5-Chloro-3,4-dihydrospiro[chromene-2,4′-piperidine]hydrochloride salt

Step 1: 1-(2-Chloro-6-hydroxyphenyl)ethanone. To a solution of3-chlorophenol (50 g, 390.62 mmol, 1.00 equiv) in DCM (500 mL) was addedDIEA (554 g, 4.29 mol, 11.00 equiv), followed by chloro(methoxy)methane(380 g, 10.00 equiv) at 20° C. The resulting mixture was allowed toreact, with stirring, for 4 h at 20° C. The reaction mixture was thenquenched with water. The separated organic phase was washed with water(2×), dried over Na₂SO₄ and then concentrated under vacuum to give1-chloro-3-(methoxymethoxy)benzene as a white oil.

To a solution of 1-chloro-3-(methoxymethoxy)benzene (24 g, 136.74 mmol,1.00 equiv, 98%) in THF (240 mL) was added TMP (21 g, 150.00 mmol, 1.10equiv). To the above solution was added n-BuLi (61 mL, 1.10 equiv, 2.5mol/L) dropwise with stirring at −75° C. over 30 min. After stirring for2 h at −75° C., the resulting mixture was reacted with Ac₂O (15.5 g,148.92 mmol, 1.10 equiv, 98%) via dropwise addition with stirring at−75° C. over 30 min. The mixture was stirred for additional 30 min atroom temperature, and then quenched by adding water. The resultingmixture was extracted with 2×300 mL of ethyl acetate. The combinedorganic layers was washed with H₂O, dried over Na₂SO₄ and concentratedunder vacuum to give 1-(2-chloro-6-(methoxymethoxy)phenyl)-ethanone as ayellow oil.

To a solution of 1-(2-chloro-6-(methoxymethoxy)phenyl)ethanone (38 g,177.03 mmol, 1.00 equiv) in THF (380 mL) was added HCl (aq. 35 g, 2.00equiv, 36%). The resulting mixture was allowed to react, with stirring,for 3 h at 65° C. The resulting mixture was extracted with ethylacetate. The organic phase was separated, dried and concentrated undervacuum to give the crude title compound.

Step 2: tert-Butyl5-chloro-4-oxo-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidine]-1′-carboxylate.A mixture of tert-butyl 4-oxopiperidine-1-carboxylate (14 g, 70.35 mmol,1.00 equiv), pyrrolidine (7 g, 98.59 mmol, 1.40 equiv) and1-(2-chloro-6-hydroxyphenyl)ethanone (12 g, 70.59 mmol, 1.00 equiv) inMeOH (150 mL) was reacted at 65° C. for 20 min. The reaction mixture wascooled to room temperature and concentrated. To the residue was added500 mL of ethyl acetate. The mixture was then washed with water (2×).The organic phase was dried over anhydrous sodium sulfate andconcentrated under vacuum to give the title compound as a white solid.

Step 3: tert-Butyl5-chloro-4-hydroxy-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidine]-1′-carboxylate.To a solution of tert-butyl5-chloro-4-oxo-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidine]-1′-carboxylate(30 g, 85.27 mmol, 1.00 equiv) in EtOH (300 mL) was added portionwiseNaBH₄ (3.3 g, 87.23 mmol, 1.02 equiv) at 25° C. over 30 min. Theresulting mixture was allowed to react, with stirring, for 1 h at roomtemperature. The reaction was then quenched with water and extractedwith ethyl acetate. The organic layers were combined, washed with H₂O(2×), dried over anhydrous sodium sulfate and concentrated under vacuumto give the title compound as a white solid.

Step 4: 5-Chloro-3,4-dihydrospiro[chromene-2,4′-piperidine]hydrochloridesalt. To a mixture of tert-butyl5-chloro-4-hydroxy-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidine]-1′-carboxylate(12.4 g, 35.04 mmol, 1.00 equiv) in trifluoroacetic acid (130 mL) wasadded triethylsilane (16.8 g, 144.48 mmol, 4.12 equiv). The resultingmixture was allowed to react, with stirring, for 5 h while thetemperature was maintained at 80° C. to reflux. The resulting mixturewas concentrated under vacuum. To the resulting residue were added 200mL of Et₂O. The resulting solids were collected by filtration to givethe TFA salt as a white solid. The TFA salt was converted to the freebase by the treatment with aqueous NaOH. The free base was thendissolved in Et₂O and reacted with HCl gas to give the title compound asa white solid.

Intermediate 2

Ethyl[5-(2-bromo-1,3-thiazol-5-yl)-2H-tetrazol-2-yl]acetate

Step 1: 2-Bromo-1,3-thiazole-5-carboxamide Into a 2 L round-bottom flaskwas added ethyl 2-bromothiazole-5-carboxylate (50.0 g, 212 mmol), THF(500 mL) and MeOH (250 mL). To this was added concentrated ammoniumhydroxide in water (590 mL) and the reaction mixture was stirred at roomtemperature for 4 h. The solvents were removed under reduced pressure,and the crude mixture poured into a separatory funnel containing brine(1 L). The aqueous layer was extracted with EtOAc (4×500 mL) and thecombined organic layers were washed with brine, dried over Na₂SO₄,filtered and concentrated under reduced pressure to give the titlecompound.

Step 2: 2-Bromo-1,3-thiazole-5-carbonitrile Into a 2 L round-bottomflask containing 2-bromo-1,3-thiazole-5-carboxamide (41.5 g, 201 mmol)in CH₂Cl₂ (1.3 L) was added triethylamine (70 mL, 502 mmol). Theresulting solution was cooled to 0° C. and trifluoroacetic anhydride (34mL, 241 mmol) was added slowly over 15 minutes. The reaction mixture wasallowed to warm to room temperature and stirred for 2 h. The reactionmixture was poured into a 3 L separatory funnel containing saturatedaqueous NaHCO₃ solution (500 mL). The aqueous layer was extracted withdichloromethane (2×1.2 L) and the combined organic layers were washedwith brine, dried over Na₂SO₄, filtered and concentrated under reducedpressure. The resulting crude reaction mixture was filtered through ashort plug of silica gel on a sintered glass funnel, washing withcopious quantities of EtOAc. The filtrate was concentrated under reducedpressure to provide the title compound.

Step 3: 5-(2-Bromo-1,3-thiazol-5-yl)-2H-tetrazole A solution of2-bromo-1,3-thiazole-5-carbonitrile (5.00 g, 26.5 mmol) in 2-propanol(75 mL) and water (38 mL) was treated with ZnBr₂ (5.96 g, 26.5 mmol) andsodium azide (2.58 g, 39.7 mmol). The reaction mixture was heated at120° C. for 5 h. The cooled reaction mixture was diluted with water (50mL) and acidified to pH=3 using aqueous 1 M HCl solution (approximately20 mL). The mixture was poured into a 500 mL separatory funnel and theaqueous layer was extracted with EtOAc (4×100 mL). The combined organiclayers were washed with brine, dried over Na₂SO₄, filtered andconcentrated under reduced pressure to provide the title compound.

Step 4: Ethyl[5-(2-bromo-1,3-thiazol-5-yl)-2H-tetrazol-2-yl]acetate Intoa 250 mL round-bottom flask containing5-(2-bromo-1,3-thiazol-5-yl)-2H-tetrazole (5.43 g, 22.5 mmol) in THF (81mL) was added triethylamine (7.2 mL, 52 mmol) and ethyl bromoacetate(3.8 mL, 34 mmol). The resulting mixture was heated at 80° C. for 1 h,and then cooled to room temperature. The reaction mixture was pouredinto a separatory funnel containing water (80 mL) and the aqueous layerwas extracted with EtOAc (2×160 mL). The combined organic layers werewashed with brine, dried over Na₂SO₄, filtered and concentrated underreduced pressure. Purification by column chromatography through silicagel, eluting with 100% hexanes to 50:50 hexanes:EtOAc as a gradientprovided the title compound as a single regioisomer. ¹H NMR (d₆-DMSO,400 MHz) 8.39 (1H, s), 5.93 (2H, s), 4.21 (2H, q, J=7.0 Hz), 1.22 (3H,t, J=7.0 Hz).

Intermediate 3

tert-Butyl[5-(2-bromo-1,3-thiazol-5-yl)-2H-tetrazol-2-yl]acetate

This compound was synthesized in a similar manner as described forethyl[5-(2-bromo-1,3-thiazol-5-yl)-2H-tetrazol-2-yl]acetate(INTERMEDIATE 2) using tert-butyl bromoacetate in place of ethylbromoacetate in step 4. ¹H NMR (CDCl₃, 400 MHz) 8.22 (1H, s), 5.32 (2H,s), 1.47 (9H, s). MS (ESI, Q⁺) m/z 346, 348 (M+1, ⁷⁹Br, ⁸¹Br).

Intermediate 4

5-Bromo-1,3,4-thiadiazole-2-carbonitrile

Step 1: Ethyl 5-bromo-1,3,4-thiadiazole-2-carboxylate To a suspension ofethyl 5-amino-1,3,4-thiadiazole-2-carboxylate in CH₃CN (0.32 M) wasadded CuBr₂ (2 equiv). The mixture turned dark green and was stirred for15 min at room temperature. t-BuONO, 90% (2 equiv) was added dropwiseover 15-20 min. The mixture became slightly warm and gas evolved afterabout 5 min and then throughout the addition. After completion of theaddition and after gas evolution subsided, the mixture was heated at 60°C. for 30 min. Solvent was then evaporated in vacuo. Water and EtOAcwere added and the mixture was stirred until the dark green colordisappeared. The organic phase became light brown and the aqueous phasewas green with insoluble material. The entire mixture was filteredthrough Celite™ and washed with EtOAc. The EtOAc layer was separated,washed with diluted brine, dried (Na₂SO₄) and concentrated to give thetitle compound. ¹H NMR (400 MHz, acetone-d₆): δ 4.52 (q, 2H), 1.43 (t,3H).

Step 2: 5-Bromo-1,3,4-thiadiazole-2-carboxamide To a solution of ethyl5-bromo-1,3,4-thiadiazole-2-carboxylate in THF (1.1 M) at roomtemperature was added concentrated NH₄OH (2.9 equiv). The mixture wasstirred at room temperature overnight and a precipitate appeared in theaqueous layer. Volatile solvent was removed in vacuo. The mixture wasdiluted with water and the precipitate was collected, washed with waterand dried under vacuum to give the title compound. ¹H NMR (400 MHz,acetone-d₆): δ 7.99 (s, 1H), 7.55 (s, 1H).

Step 3: 5-Bromo-1,3,4-thiadiazole-2-carbonitrile To a solution of5-bromo-1,3,4-thiadiazole-2-carboxamide and Et₃N (2.3 equiv) in THF (0.5M) at 0° C. was added TFAA (1.1 equiv). The mixture was then warmed toroom temperature and stirred for 30 min. Solvent was evaporated invacuo. The resulting residue was diluted with water. The precipitate wascollected, washed with water, and dried to give the title compound.

Intermediate 5

Ethyl[5-(5-bromo-1,3,4-thiadiazol-2-yl)-2H-tetrazol-2-yl]acetate

To a suspension of 5-bromo-1,3,4-thiadiazole-2-carbonitrile (1 g, 5mmol) and ZnBr₂ (1.1 g, 5 mmol) in i-PrOH (10 mL) and H₂O (5 mL) wasadded NaN₃ (0.65 g, 10 mmol) in a sealed tube. The mixture was stirredat 120° C. overnight and then cooled to room temperature. The mixturewas adjusted to pH=4 with HCl (2 M) and extracted with EtOAc (50 mL×3).The combined organic layers was dried over Na₂SO₄, filtered andconcentrated in vacuum to afford the crude5-(5-bromo-1,3,4-thiadiazol-2-yl)-1H-tetrazole. ¹³C NMR (DMSO, 300 MHz):δ 159.12, 150.65, 142.84.

To a solution of 5-(5-bromo-1,3,4-thiadiazol-2-yl)-1H-tetrazole (1 g,4.3 mmol) in DMF (20 mL) was added Cs₂CO₃ (2.1 g, 6.45 mmol) and ethylbromoacetate (0.95 mL, 8.6 mmol). The resulting solution was stirred at90° C. for 1 hour. The mixture was partitioned between EtOAc (100 mL)and water (200 mL). The combined organic layers were dried overanhydrous Na₂SO₄, filtered and evaporated in vacuo. Chromatography oversilica afforded the title compound as a white solid, contaminated withthe 1-alkylated isomerethyl[5-(5-bromo-1,3,4-thiadiazol-2-yl)-1H-tetrazol-1-yl]acetate. ¹HNMR(CDCl₃, 300 MHz): δ 5.70 (s, 2H), 4.26 (q, J=7 Hz, 2H), 1.28 (t, J=7 Hz,3H).

Intermediate 6

tert-Butyl[5-(5-bromo-1,3,4-thiadiazol-2-yl)-2H-tetrazol-2-yl]acetate

The title compound was prepared in a similar manner as described forIntermediate 5 from 5-(5-bromo-1,3,4-thiadiazol-2-yl)-1H-tetrazole andtert-butyl bromoacetate. The isolated title compound was contaminatedwith ˜20% oftert-butyl[5-(5-bromo-1,3,4-thiadiazol-2-yl)-1H-tetrazol-1-yl]acetate.¹HNMR (CDCl₃ 300 MHz): δ 5.43 (s, 2H), 1.47 (s, 9H).

Intermediate 7

tert-Butyl[5-(3-bromo-4,5-dihydroisoxazol-5-yl)-2H-tetrazol-2-yl]acetate

Step 1: Ethyl 3-bromo-4,5-dihydroisoxazole-5-carboxylate To around-bottom flask containing hydroxycarbonimidic dibromide (100 g, 490mmol) was slowly added DMF (300 mL) followed by ethyl acrylate (59 g,590 mmol). The mixture was cooled to −10° C. and then a solution ofKHCO₃ (99 g, 990 mmol) in water (400 mL) was added dropwise over 90 min,at a rate which maintained the internal temperature below 0° C. Stirringwas continued at 0° C. for 1.5 h. The reaction mixture was poured into a4 L separatory funnel containing water (500 mL) and the aqueous layerwas extracted with MTBE (3×500 mL). The combined organic layers werewashed with brine, dried over MgSO₄, filtered and concentrated underreduced pressure to give a yellow oil which was used directly in Step 2.

Step 2: 3-Bromo-4,5-dihydroisoxazole-5-carboxamide Ethyl3-bromo-4,5-dihydroisoxazole-5-carboxylate (109 g, 490 mmol) was addedto a 1 L round-bottom flask containing 2.0 M NH₃ in MeOH (295 mL). Thereaction mixture was heated at 50° C. for 2.5 h and then cooled to roomtemperature and stirred overnight for 16 h. The resulting slurry wasdiluted with 500 mL of diethyl ether and stirred in an ice-bath for 1 h.The product was isolated by filtration under vacuum, affording the titlecompound as a tan solid. ¹H NMR (CDCl₃, 400 MHz): δ 6.70 (1H, bs), 5.92(1H, bs), 5.06 (1H, dd, J=11.0, 6.5 Hz), 3.64-3.51 (2H, m). MS (ESI, Q⁺)m/z 193, 195 (M+1, ⁷⁹Br, ⁸¹Br).

Step 3: 3-Bromo-4,5-dihydroisoxazole-5-carbonitrile To a solution of3-bromo-4,5-dihydroisoxazole-5-carboxamide (30.0 g, 155 mmol) in THF(360 mL) was added triethylamine (43.0 mL, 311 mmol). The solution wascooled to 0° C. and TFAA (33.0 mL, 233 mmol) was added slowly over 20min, at a rate which maintained the internal temperature below 15° C.The reaction mixture was stirred at 0° C. for 1 h. The reaction mixturewas poured into a 2 L separatory funnel containing water (500 mL) andthe aqueous layer was extracted with MTBE (3×500 mL). The combinedorganic layers were washed with a saturated aqueous NaHCO₃ solution(2×250 mL) and brine, dried over MgSO₄, filtered and concentrated underreduced pressure to afford the title compound.

Step 4: 5-(3-Bromo-4,5-dihydroisoxazol-5-yl)-2H-tetrazole To a 2 Lround-bottom flask equipped with a reflux condenser, heating mantle andunder N₂, was added 3-bromo-4,5-dihydroisoxazole-5-carbonitrile (39.4 g,225 mmol), zinc oxide (1.8 g, 23 mmol), THF (40 mL) and water (200 mL).To this solution was added in slowly a solution of sodium azide (16 g,250 mmol) in water (10 mL) over 5 min and the mixture was warmed to 75°C. for 16 h. Heating was applied at a rate in where the internaltemperature of the reaction mixture did not exceed 80° C. The reactionmixture was cooled to 0° C. and acidified to pH 3-4 with slow additionof 2 N aqueous HCl solution. During the acidification, the internaltemperature was maintained below 5° C. The reaction mixture was pouredinto a 2 L separatory funnel and the aqueous layer was extracted withEtOAc (3×500 mL). The combined organic layers were washed with brine,dried over MgSO₄, filtered and concentrated under reduced pressure toafford the title compound.

Step 5:tert-Butyl[5-(3-bromo-4,5-dihydroisoxazol-5-yl)-2H-tetrazol-2-yl]acetateTo a 2 L round-bottom flask equipped with a reflux condenser, heatingmantle and under N₂ was added5-(3-bromo-4,5-dihydroisoxazol-5-yl)-2H-tetrazole (49 g, 225 mmol) andTHF (500 mL). Triethylamine (53 mL, 383 mmol) was added to the mixtureand the solution was heated to 55° C. while tert-butyl bromoacetate (66g, 338 mmol) was added. The mixture was heated at 55° C. for 1 h andthen cooled to room temperature. The reaction mixture was poured into a2 L separatory funnel containing 1 N aqueous HCl solution (500 mL) andthe aqueous layer was extracted with EtOAc (3×500 mL). The combinedorganic layers were washed with brine, dried over MgSO₄, filtered andconcentrated under reduced pressure. Purification by columnchromatography through Iatrobead™ silica gel, eluting with 75:15:5hexanes/EtOAc/CH₂Cl₂, afforded the title product in a greater than 10:1regioisomeric purity. ¹H NMR (CDCl₃, 400 MHz): δ 5.98 (1H, dd, J=11.0,7.5 Hz), 5.35 (2H, s), 3.87 (1H, dd, J=17.5, 7.5 Hz), 3.70 (1H, dd,J=17.5, 11.0 Hz), 1.50 (9H, s). MS (ESI, Q⁺) m/z 332, 334 (M+1, ⁷⁹Br,⁸¹Br).

Intermediate 8

5-(Trifluoromethoxy)-3,4-dihydrospiro[chromene-2,4′-piperidinium]chloride

Step 1: 1-Bromo-2-(methoxymethoxy)-4-(trifluoromethoxy)benzene To a coldsolution of 2-bromo-5-(trifluoromethoxy)phenol (50 g, 195 mmol) andHunig's base (120 mL, 687 mmol) in CH₂Cl₂ (100 mL) at −78° C. (frozen asa white cake) was added MOM-Cl (35 mL, 461 mmol). The white cake waswarmed to room temperature and stirred overnight. The mixture wasdiluted with water (150 mL), the mixture was stirred for 15 min andextracted with CH₂Cl₂ (2×). The CH₂Cl₂ extracts were combined, washedwith brine, dried (Na₂SO₄), filtered and concentrated. The resultingresidue was purified by column chromatography on SiO₂ (isocratic 10%EtOAc/hexanes) to afford the title product as a colorless oil. ¹H NMR(400 MHz, acetone-d₆): δ 7.74 (d, 1H), 7.22 (d, 1H), 6.99 (dd, 1H), 5.40(s, 2H), 3.52 (s, 3H).

Step 2: 1-[2-(Methoxymethoxy)-6-(trifluoromethoxy)phenyl]ethanone Asolution of 1-bromo-2-(methoxymethoxy)-4-(trifluoromethoxy)benzene (60g, 198 mmol) in THF (500 mL) at −100° C. was treated by a slow additionof t-BuLi in pentane (1.7M) (1.3 equiv) over 45 min by keeping internaltemperature between −97° C. to −102°. After 1 h at −100° C., followingthe end of the addition of t-BuLi, diisopropylamine (0.1 equiv) wasadded at −100° C. and the mixture was allowed to warm up and thenstirred for 3 h at −90° C. The reaction mixture was cooled back to −100°C., then acetic anhydride (24 mL, 254 mmol) was added drop wise keepingthe internal temperature below −95° C. The final suspension was warmedto 0° C. The mixture was poured into water (300 mL) and the volatileswere evaporated under reduced pressure. More water (50 mL) was added andthe aqueous media was extracted with EtOAc (350 mL), and washed withbrine. The aqueous phases were back extracted with EtOAc. The organiclayers were combined, dried (MgSO₄), filtered and evaporated underreduced pressure. The resulting material was purified on chromatographycolumn on SiO₂ (gradient 0 to 20% EtOAc/hexanes) to afford the titlecompound as an colorless oil. ¹H NMR (500 MHz, acetone-d₆): δ 7.51 (t,1H), 7.26 (d, 1H), 7.07 (d, 1H), 5.33 (s, 2H), 3.48 (s, 3H), 2.51 (s,3H).

Step 3: 1-[2-Hydroxy-6-(trifluoromethoxy)phenyl]ethanone To a solutionof 1-[2-(methoxymethoxy)-6-(trifluoromethoxy)phenyl]ethanone (48 g, 181mmol) in i-PrOH (60 mL) was added aq HCl 37% (8 mL, 97 mmol). Thereaction mixture was heated to 50° C. for 2 h, and then poured intowater. The reaction mixture was cooled to 0° C., pentane was added (400mL) and the mixture was poured into 0.5 N HCl (500 mL). The organiclayer was separated, washed with 0.5 N HCl (4×250 mL) and brine. Theaqueous phases were back extracted with pentane (400 mL). The organiclayers were combined, dried (MgSO₄), filtered, cooled to 0° C. andevaporated under reduced pressure by keeping the water bath at 0° C. togive the title compound as a yellow oil containing some i-PrOH. Thecrude material was used such as in the next step. ¹H NMR (400 MHz,acetone-d₆): δ 12.08 (br s, 1H), 7.60 (t, 1H), 7.02 (d, 1H), 6.97 (d,1H), 2.70 (s, 3H).

Step 4: tert-Butyl4-oxo-5-(trifluoromethoxy)-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidine]-1′-carboxylateA mixture of 75% in weight of1-[2-hydroxy-6-(trifluoromethoxy)phenyl]ethanone (50 g, 170 mmol),1-BOC-4-piperidone (32 g, 161 mmol) in xylene (50 mL), was treated withpyrrolidine (2.6 mL, 32.1 mmol). The mixture was heated to 105° C. for14 h by removing water and volatile solvents. The crude reaction waspurified by column chromatography on SiO₂ (isocratic 100% hexanes andthen a slow gradient from 5 to 20% EtOAc/hexanes). After evaporation ofthe solvents, the resulting material was triturated with hexanes at −78°C. The cold suspension was filtered and trituration was repeated toafford the title compound as a white solid. ¹H NMR (400 MHz,acetone-d₆): δ 7.67 (t, 1H), 7.19 (dd, 1H), 7.01 (d, 1H), 3.89 (br d,2H), 3.24 (br s, 2H), 2.87 (s, 2H), 2.06-1.95 (m, 2H), 1.79-1.69 (m,2H), 1.46 (s, 9H).

Step 5: tert-Butyl4-hydroxy-5-(trifluoromethoxy)-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidine]-P-carboxylateInto a 500 mL flask, a mixture of tert-butyl4-oxo-5-(trifluoromethoxy)-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidine]-1′-carboxylate(15 g, 37.4 mmol) in THF (50 mL) and MeOH (50 mL) was treated with NaBH₄(2.1 g, 56.1 mmol) at −78° C., then warmed and stirred for 1 h at 0° C.Acetone was added to quench the excess hydride and the volatiles wereevaporated under reduced pressure. Water and aq NaHCO₃ were added, andthe aqueous media was extracted with EtOAc. The organic layer was washedwith aq NaHCO₃ (2×), and brine. The aqueous phases were back extractedwith EtOAc. The organic layers were combined, dried (MgSO₄), filteredand concentrated to afford the title compound as an off-white solid. Thecrude material was used such as in the next step. ¹H NMR (400 MHz,acetone-d₆): δ 7.33 (t, 1H), 6.92 (d, 2H), 5.09-5.05 (m, 1H), 4.50 (d,1H), 3.85 (d, 1H), 3.76 (d, 1H), 3.36 (br s, 1H), 3.16 (br s, 1H),2.25-2.16 (m, 2H), 2.04 (dd, 1H), 1.78-1.69 (m, 3H), 1.47 (s, 9H).

Step 6:5-(Trifluoromethoxy)-3,4-dihydrospiro[chromene-2,4′-piperidinium]chlorideInto a 1 L flask, a cold (−78° C.) solution of tert-butyl4-hydroxy-5-(trifluoromethoxy)-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidine]-1′-carboxylate(15 g, 37.2 mmol) in CH₂Cl₂ (80 mL) was treated with Et₃SiH (24 mL, 150mmol) followed by TFA (40 mL). The final mixture was warmed to roomtemperature and heated to reflux (oil bath at 50° C.) for 24 h. Theresulting mixture was concentrated under vacuum. To the resultingresidue was added 4 M HCl in dioxane (30 mL) and the solution wasconcentrated. This treatment with HCl was repeated three times. Theresulting residue was triturated with Et₂O, and the white solid wascollected by filtration and dried to afford the title compound. Thesupernatant was concentrated and treated again with 4 M HCl as describedabove to afford more of the title compound as a white solid aftertrituration with Et₂O/heptane. Alternatively, the title compound may besynthesized according to the following procedure: To a solution oftert-butyl4-hydroxy-5-(trifluoromethoxy)-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidine]-1′-carboxylate(23.6 g, 58.5 mmol) in degassed EtOAc (234 mL) were added dropwisePd(OH)₂ catalyst (4.72 g, 6.72 mmol) and MsOH (22.49 g, 234 mmol). Thereaction was shaken on a Parr shaker under 50 psi of H₂ overnight. Themixture was then filtered over Solka Flok™ under a flow of N₂ and rinsedwith 600 mL of EtOAc. The resulting filtrate was washed with 2 N NaOH(2×), dried over MgSO₄ and concentrated under reduced pressure to givethe title compound. LC-MS: m/z=288.1 (MH+). ¹H NMR (400 MHz, DMSO-d₆): δ9.12 (br s, 1H), 9.01 (br s, 1H), 7.23 (t, 1H), 6.92-6.86 (m, 2H),3.23-3.12 (m, 2H), 3.11-2.91 (m, 2H), 2.70 (t, 2H), 1.87-1.78 (m, 6H).

Intermediate 9

4-Oxo-5-(trifluoromethoxy)-3,4-dihydrospiro[chromene-2,4′-piperidinium]chloride

A mixture of tert-butyl4-oxo-5-(trifluoromethoxy)-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidine]-F-carboxylate(1.0 g, 2.491 mmol) (from Intermediate 8, Step 4) in 1,4-dioxane (25 mL)was treated with 4 M HCl in dioxane (25 mL, 100 mmol). The suspensionwas heated for 30-60 min before the mixture was evaporated to dryness.The residue was triturated with Et₂O/heptane, filtered and dried toafford the title compound as a beige solid. ¹H NMR (500 MHz, DMSO-d₆): δ8.96 (br s, 1H), 8.72 (br s, 1H), 7.70 (t, 1H), 7.23 (d, 1H), 7.05 (d,1H), 3.26-3.17 (m, 2H), 3.17-3.04 (m, 2H), 2.96 (s, 2H), 2.11 (d, 2H),1.97-1.86 (m, 2H).

Intermediate 10

5-Bromo-3,4-dihydrospiro[chromene-2,4′-piperidinium]chloride

Step 1: 1-Bromo-3-(methoxymethoxy)benzene To a solution of 3-bromophenol(10 g, 57.8 mmol) and Hunig's base (35.7 mL, 205 mmol) in CH₂Cl₂ (30 mL)at −78° C., was added MOM-Cl (10.98 mL, 145 mmol). The mixture waswarmed to room temperature and stirred overnight. The mixture wasdiluted with water (150 mL), stirred for 15 min and extracted withCH₂Cl₂ (2×). The CH₂Cl₂ extract was washed with brine, dried (Na₂SO₄),filtered and concentrated to give a yellow oil. The material waspurified by column chromatography on SiO₂ (gradient from 0 to 20%EtOAc/hexanes) to give the title compound as a colorless oil.

Step 2: 1-[2-Bromo-6-(methoxymethoxy)phenyl]ethanone To a solution ofdiisopropylamine (9.85 mL, 69.1 mmol) in THF (100 mL) at −78° C. wasslowly added 2.5 M n-BuLi (29.9 mL, 74.9 mmol). The solution was warmedand stirred 20 min at 0° C., cooled to −100° C. before the slow additionof the cold THF (40 mL) solution of 1-bromo-3-(methoxymethoxy)benzene(12.5 g, 57.6 mmol) via a cannula. The mixture was stirred for 2 h at−100° C., keeping the internal temperature kept between −94° C. and 101°C. Then acetic anhydride (10.00 mL, 106 mmol) was added drop wise to thereaction mixture and internal temperature was kept below −95° C. Thefinal white suspension was warmed to room temperature. Then water (100mL) was added and the volatile materials were evaporated under reducedpressure. More water was added and the aqueous media was extracted withEtOAc, and washed with brine. The aqueous phases were back extractedwith EtOAc. The organic layers were combined, dried (Na₂SO₄), filteredand evaporated under reduced pressure. The residue was purified onchromatography column on SiO₂ (120 g, gradient 0 to 15% EtOAc/hexanes)to afford the title compound as a colorless oil.

Step 3: 1-(2-Bromo-6-hydroxyphenyl)ethanone To a solution of1-[2-bromo-6-(methoxymethoxy)phenyl]ethanone (12.6 g, 48.6 mmol) in2-propanol (100 mL) was added aq HCl (37%, 20 mL, 244 mmol). Thesolution was heated to 65° C. for 4 h. Then, the volatiles wereevaporated under reduced pressure. Water was added and the aqueous mediawas extracted with EtOAc, and washed with brine. The aqueous phases wereback extracted with EtOAc. The organic layers were combined, dried(Na₂SO₄), filtered and evaporated under reduced pressure. The resultingresidue was purified by trituration with heptane to afford the titlecompound as a beige solid.

Step 4: tert-Butyl5-bromo-4-oxo-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidine]-1′-carboxylateA mixture of 1-(2-bromo-6-hydroxyphenyl)ethanone (8.81 g, 41.0 mmol),1-boc-4-piperidone (8.82 g, 44.2 mmol) and pyrrolidine (0.847 mL, 10.24mmol) in xylene (70 mL) was heated to 100° C. for 16 h by removingwater. The residue was purified by column chromatography on SiO₂(gradient from 0 to 30% EtOAc/hexanes), followed by a co-evaporationwith Et₂O/heptane to give the title compound as a beige solid. LC-MS:m/z=418.0, 420.0 (M+Na).

Step 5: tert-Butyl5-bromo-4-hydroxy-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidine]-1′-carboxylateA mixture of tert-butyl5-bromo-4-oxo-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidine]-1′-carboxylate(2.04 g, 5.15 mmol) in THF (20 mL) and MeOH (20 mL) was treated withNaBH₄ (0.390 g, 10.30 mmol) at 0° C. The suspension was warmed to roomtemperature and stirred for 1 h. Acetone was added to quench the excessof hydride and the volatiles were evaporated under reduced pressure.Water was added and the aqueous media was extracted with EtOAc. Theorganic layer was washed with water, aq NaHCO₃, and brine. The aqueousphases were back extracted with EtOAc and the organic layers werecombined, dried (Na₂SO₄), filtered and concentrated to give the titlecompound as an off-white solid.

Step 6: 5-Bromo-3,4-dihydrospiro[chromene-2,4′-piperidinium]chloride Acold solution of tert-butyl5-bromo-4-hydroxy-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidine]-1′-carboxylate(514 mg, 1.291 mmol) in CH₂Cl₂ (8 mL) was treated with triethylsilane(1.649 mL, 10.32 mmol), followed by TFA (4 mL). The final mixture waswarmed to room temperature and then heated to 80° C. for 5.5 h. Theresulting mixture was concentrated under vacuum. To the resultingresidue was added 4 M HCl in dioxane (4 mL) and the solution wasconcentrated (repeated twice). Then, to the residue was added Et₂O and awhite solid precipitate was observed. The suspension was trituratedunder ultrasound, filtered and dried to give the title compound as awhite solid. LC-MS: m/z=284.0, 282.0 (MH+). ¹H NMR (500 MHz, DMSO-d₆): δ8.76 (br s, 2H), 7.19 (d, 1H), 7.09 (t, 1H), 6.90 (d, 1H), 3.24-3.16 (m,2H), 3.07 (td, 2H), 2.70 (t, 2H), 1.92-1.77 (m, 6H).

Intermediate 11

5-Bromospiro[chromene-2,4′-piperidin]-4(3H)-one A mixture of tert-butyl5-bromo-4-oxo-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidine]-1′-carboxylate(4.6 g, 10.45 mmol) (Intermediate 10, Step 4) in 1,4-dioxane (7 mL) wastreated with 4 M HCl in dioxane (50 mL, 200 mmol). The suspension washeated with a heat gun for 5-10 min before the mixture was evaporated todryness. The HCl salt was neutralized with 1 N NaOH and the aqueousphase was extracted with MTBE. The organic layer was washed with water,brine. The aqueous phases were back extracted with MTBE. The organiclayers were combined, dried (MgSO₄), filtered and concentrated. Theresidue was triturated with heptane, filtered and dried to afford thetitle compound as a pink solid. LC-MS: m/z=296.0, 298.0 (MH+). ¹H NMR(500 MHz, DMSO-d₆): δ 7.40 (t, 1H), 7.28 (d, 1H), 7.08 (d, 1H), 2.84 (s,2H), 2.85-2.75 (m, 2H), 2.68 (dt, 2H), 1.80-1.71 (m, 2H), 1.63-1.55 (m,2H).

Intermediate 12

8-Chloro-3,4-dihydrospiro[chromene-2,4′-piperidinium]chloride

Step 1: tert-Butyl8-chloro-4-oxo-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidine]-1′-carboxylateA mixture of 1-(3-chloro-2-hydroxyphenyl)ethanone (500 mg, 2.93 mmol),1-boc-4-piperidone (584 mg, 2.93 mmol) and pyrrolidine (61 pt, 0.738mmol) in Xylene (4 mL) was heated to 100° C. for 20 h. The reactionmixture was purified by column chromatography on SiO₂ (40 g, gradientfrom 0 to 40% EtOAc/hexanes) to afford the title compound as a whitesolid. LC-MS: m/z=376.1, 374.1 (M+Na).

Step 2: tert-Butyl8-chloro-4-hydroxy-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidine]-1′-carboxylateA mixture of tert-butyl8-chloro-4-oxo-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidine]-1′-carboxylate(910 mg, 2.59 mmol) in THF (10 mL) and MeOH (10 mL) was treated withNaBH₄ (196 mg, 5.17 mmol) at 0° C. The suspension was warmed to roomtemperature and stirred for 1 h. Acetone was added to quench the excessof hydride and the volatile evaporated under reduced pressure. Water wasadded and the aqueous media was extracted with EtOAc. The organic layerwas washed with water, aq NaHCO₃, and brine. The aqueous phases wereback extracted with EtOAc and the organic layers were combined, dried(Na₂SO₄), filtered and concentrated to give the title compound as afoamy white solid. LC-MS: m/z=376.1, 378.1 (M+Na).

Step 3: 8-Chloro-3,4-dihydrospiro[chromene-2,4′-piperidinium]chlorideTFA (10 mL) was added to tert-butyl8-chloro-4-hydroxy-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidine]-1′-carboxylate(905 mg, 2.56 mmol) and an exotherm was observed. Due to the exotherm,the solution was cooled rapidly to 0° C. and it was treated withtriethylsilane (1.634 mL, 10.23 mmol). The mixture was heated to 80° C.for 1.5 h. The resulting mixture was concentrated under vacuum. To theresidue was added 4 M HCl in dioxane (4 mL) and the solution wasconcentrated (this was repeated twice). Then, to the residue was addedEt₂O and the white solid was triturated under ultrasound, filtered anddried to give the title compound. LC-MS: m/z=238.1, 240.1 (MH+). ¹H NMR(500 MHz, DMSO-d₆): δ 8.82 (br s, 2H), 7.27 (d, 1H), 7.11 (d, 1H), 6.88(t, 1 H), 3.29-3.22 (m, 2H), 3.05 (td, 2H), 2.81 (t, 2H), 1.95-1.79 (m,6H).

Intermediate 13

8-Chloro-4-oxo-3,4-dihydrospiro[chromene-2,4′-piperidinium]chloride Amixture of tert-butyl8-chloro-4-oxo-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidine]-1′-carboxylate(877 mg, 2.493 mmol) (Intermediate 12, Step 1) in 1,4-dioxane (4 mL) wastreated with 4 M HCl in dioxane (6 mL, 24.00 mmol). The suspension washeated with heat gun for 5-10 min before the mixture was evaporated todryness. The residue was triturated with Et₂O, filtered and dried togive the title compound as a white solid. LC-MS: m/z=252.0, 254.0 (MH+).¹H NMR (400 MHz, DMSO-d₆): δ 8.98 (br s, 2H), 7.82 (d, 1H), 7.75 (d,1H), 7.14 (t, 1H), 3.27 (d, 2H), 3.10-2.99 (m, 4H), 2.16 (d, 2H),2.02-1.89 (m, 2H).

Intermediate 14

5-Iodo-3,4-dihydrospiro[chromene-2,4′-piperidinium]chloride

Step 1: tert-Butyl5-iodo-4-oxo-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidine]-1′-carboxylateFollowing literature reference J. Am. Chem. Soc. 2002, 124, 14844-14845,dioxane (30 mL) was added to a mixture of tert-butyl5-bromo-4-oxo-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidine]-1′-carboxylate(2.4 g, 6.06 mmol) (Intermediate 10, Step 4), NaI (1.952 g, 13.02 mmol),CuI (0.173 g, 0.908 mmol) and(R,R)-(−)-N,N′-dimethyl-1,2-cyclohexanediamine (0.258 g, 1.817 mmol).The reaction mixture was heated to 120° C. for 24 h, diluted with EtOAcand the resulting suspension was filtered through a pad of SiO₂ byeluting with 100% EtOAc. After concentration, the residue was purifiedby flash chromatography on SiO₂ (50 g, gradient from 0% to 50%EtOAc/hexanes) to afford the title compound as a yellow oil. LC-MS:m/z=466.1 (M+Na)

Step 2: tert-Butyl4-hydroxy-5-iodo-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidine]-1′-carboxylateA mixture of tert-butyl5-iodo-4-oxo-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidine]-1′-carboxylate(800 mg, 1.805 mmol) in THF (8 mL) and MeOH (8.00 mL) was treated withNaBH₄ (137 mg, 3.61 mmol) at 0° C. The suspension was warmed to roomtemperature and stirred for 1 h. Then acetone was added to quench theexcess of hydride and the volatiles were evaporated under reducedpressure. Water was added to the residue and the aqueous media wasextracted with EtOAc. The organic layer was washed with water, aqNaHCO₃, and brine. The aqueous phases were back extracted with EtOAc andthe organic layers were combined, dried (Na₂SO₄), filtered andconcentrated to give the title compound as an off-white solid. LC-MS:m/z=468.0 (M+Na).

Step 3: 5-Iodo-3,4-dihydrospiro[chromene-2,4′-piperidinium]chloride Acold solution of tert-butyl4-hydroxy-5-iodo-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidine]-1′-carboxylate(800 mg, 1.797 mmol) in CH₂Cl₂ (10 mL) was treated with triethylsilane(2.296 mL, 14.37 mmol) followed by TFA (5 mL). The final mixture waswarmed to room temperature, then heated to 80° C. for 10 h andconcentrated under vacuum. To the residue was added 4 M HCl in dioxane(10-15 mL) and the solution was concentrated again (this was repeatedthree times). To the resulting residue was added Et₂O and the whitesolid was triturated under ultrasound, filtered and dried to afford thetitle compound as a white solid. (LC-MS: m/z=330.0 (MH+)). ¹H NMR (500MHz, DMSO-d₆): δ 8.61 (br s, 2H), 7.44 (dd, 1H), 6.94-6.88 (m, 2H),3.24-3.16 (m, 2H), 3.07 (td, 2 H), 2.61 (t, 2H), 1.92-1.74 (m, 6H).

Intermediate 15

5-Iodo-4-oxo-3,4-dihydrospiro[chromene-2,4′-piperidinium]chloride Amixture of tert-butyl5-iodo-4-oxo-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidine]-1′-carboxylate(718 mg, 1.296 mmol; Intermediate 14, Step 1) in 1,4-dioxane (4 mL) wastreated with 4 M HCl in dioxane (8 mL, 32 mmol). The suspension washeated with heat gun for 20-30 min before the mixture was evaporated todryness. The residue was triturated with 1,4-dioxane, filtered and driedto give the title compound as an off-white solid. LC-MS: m/z=344.0(MH+). ¹H NMR (500 MHz, DMSO-d₆): δ 8.84 (br s, 1H), 8.67 (br s, 1H),7.62 (dd, 1H), 7.18 (t, 1H), 7.11 (dd, 1H), 3.16-3.09 (m, 2H), 3.08-2.97(m, 2H), 2.92 (s, 2H), 2.01 (d, 2H), 1.88-1.77 (m, 2H).

Intermediate 16

8-Chlorospiro[isochromene-3,4′-piperidin]-1(4H)-one To a solution of2-bromo-6-chloro-benzoic acid (1.50 g, 6.37 mmol) in THF (25 mL) at −78C was added n-butyl lithium (2.5 M in hexanes, 5.35 mL, 13.38 mmol)dropwise. The solution was stirred for 1 h before1-oxa-6-aza-spiro[2.5]octane-6-carboxylic acid tert-butyl ester (1.63 g,7.64 mmol; prepared as described in literature procedure Sabbani, S. etal., Bioorg. Med. Chem. Lett. 2008, 18, 5804-5808) in THF (8.5 mL) wasadded to the mixture. The stirring was continued for 5 h at −78 C, thenleft overnight and warmed to room temperature. The reaction mixture wasquenched with NaOH (1 N, 30 mL). The volatiles were removed underreduced pressure. The resulting aqueous layer was washed with MTBE (15mL) and acidified with 6N HCl (30 mL). The lactonization anddeprotection were achieved by heating to 60° C. for 3 h. The resultingmixture was cooled in an ice bath to keep the temperature below 20° C.as it was basified with 10 N NaOH to pH 10-12. The aqueous layer wasextracted with IPA (2×60 mL). The combined organic layers were washedwith brine, dried over anhydrous MgSO₄ and concentrated under reducedpressure. The residue was purified by Combiflash™ chromatography (aminecolumn, elution with 0-10% MeOH/DCM) to afford the title compound assolid. ¹H NMR (CDCl₃, 400 MHz) 7.45-7.40 (2H, m), 7.19-7.14 (1H, m),4.36 (1H, br), 3.17-3.09 (2H, m), 3.05 (2H, s), 2.94 (2H, ddd),1.96-1.88 (2H, m), 1.74 (2H, ddd). MS (ESI, Q⁺) m/z 252.0, 254.0 (M+1,³⁵Cl, ³⁷Cl).

Intermediate 17

Ethyl{5-[2-(4-oxopiperidin-1-yl)-1,3-thiazol-5-yl]-2H-tetrazol-2-yl}acetate

Step 1:Ethyl{5-[2-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-1,3-thiazol-5-yl]-2H-tetrazol-2-yl}acetate.The title compound was prepared in a similar manner as that describedfor Example 13 (step 1) from Intermediate 2 and1,4-dioxa-8-azaspiro[4.5]decane.

Step 2:Ethyl{5-[2-(4-oxopiperidin-1-yl)-1,3-thiazol-5-yl]-2H-tetrazol-2-yl}acetate.To a solution ofethyl{5-[2-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-1,3-thiazol-5-yl]-2H-tetrazol-2-yl}acetate(377 mg, 0.99 mmol) in THF (4.95 mL) was added 1N HCl (1.09 mL, 1.09mmol). The reaction mixture was heated to 65° C. for 3 h. The volatileswere evaporated under reduced pressure. The mixture was diluted withwater (20 mL) and extracted with EtOAc (3×5 mL). The combined organicfractions were dried over MgSO₄, filtered and evaporated under reducedpressure. The residue was purified by Combiflash™ chromatography (SiO₂,12 g, elution with 10-70% EtOAc/hexanes over 40 min) to afford the titlecompound as solid. ¹H NMR (500 MHz, DMSO-d₆): δ 7.92 (s, 1H), 5.85 (s,2H), 4.22 (q, 2H), 3.90 (t, 4H), 2.57 (t, 4H), 1.23 (t, 3 H). MS (+ESI):m/z 337.1 (MH+).

Intermediate 18

Ethyl (2-oxo-2,3-dihydro-1H-imidazol-1-yl)acetate

Step 1: Ethyl N-{[(2,2-dimethoxyethyl)amino]carbonyl}glycinate To asolution of ethyl isocyanatoacetate (8.84 mL, 77 mmol) in CH₂Cl₂ (100mL) at 0° C. was added aminoacetaldehyde dimethyl acetal (8.86 mL, 81mmol) over a period of 10 min. The mixture was further stirred for 30min, quenched with water. The CH₂Cl₂ layer was separated, washed withwater, dried (Na₂SO₄) and concentrated to give the crude title compoundas an oil.

Step 2: Ethyl (2-oxo-2,3-dihydro-1H-imidazol-1-yl)acetate To a solutionof ethyl N-{[(2,2-dimethoxyethyl)amino]carbonyl}glycinate (16 g, 68.3mmol) in acetic acid (20 mL) was added 80% aqueous formic acid (80 mL,1669 mmol). The mixture was stirred at 65° C. for 1 h. Most volatilematerials were removed in vacuo. The residue was diluted with smallamount of water (˜10 to 20 mL) and extracted with EtOAc (3×50 mL). Thecombined EtOAc extracts were concentrated and dried in vacuo. Theresidue was swished with Et₂O, filtered and dried to give the titlecompound as a pale yellow solid. ¹H NMR (500 MHz, acetone-d₆): δ 9.49(s, 1H), 6.45 (d, 1H), 6.40 (d, 1H), 4.39 (s, 2H), 4.23-4.14 (q, 2H),1.29-1.23 (t, 3H).

Intermediate 19

5-(Trifluoromethoxy)spiro[chromene-2,4′-piperidinium]chloride A mixtureof tert-butyl4-hydroxy-5-(trifluoromethoxy)-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidine]-1′-carboxylate(0.92 g, 2.29 mmol; Intermediate 8, Step 5) was diluted with 4 M HCl indioxane (60 mL, 240 mmol) and heated to 120° C. for 3-4 days. Thesuspension was concentrated under vacuum. The residue was diluted withMTBE and the salt was treated with 1 N NaOH. The organic layer wasseparated and washed twice with water and brine. The aqueous phases wereback extracted with MTBE. The organic layers were combined, dried(MgSO₄), treated with active charcoal, filtered through a Celite™ pad,concentrated and treated with 4 M HCl in dioxane, and evaporated todryness. The residue was triturated with Et₂O/heptane, filtered anddried to afford the title compound as a beige solid. LC-MS: m/z=286.2(MH+). ¹H NMR (400 MHz, DMSO-d₆): δ 9.11 (br s, 1H), 8.99 (br s, 1H),7.32 (t, 1H), 7.02 (d, 1H), 6.98 (d, 1H), 6.68 (d, 1H), 6.03 (d, 1H),3.30-3.10 (m, 4H), 2.13-2.01 (m, 2H), 2.03-1.88 (m, 2H).

Intermediate 20

5-(Trifluoromethoxy)-3,4-dihydrospiro[chromene-2,4′-piperidinium]chloride-d₂

Step 1: tert-Butyl4-hydroxy-5-(trifluoromethoxy)-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidine]-1′-carboxylate-d₁The title compound was prepared, as a tan solid, starting fromtert-butyl4-oxo-5-(trifluoromethoxy)-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidine]-1′-carboxylate(600 mg, 1.50 mmol; Intermediate 8, Step 4) through 2 synthetic steps inthe same manner as described for Intermediate 8, but using deuteratedreagents (NaBD₄, MeOD, Et₃SiD, TFA-d) for Steps 5 and 6. LC-MS:m/z=290.1 (MH+). ¹H NMR (400 MHz, DMSO-d₆): δ 8.94 (br s, 1H), 8.81 (brs, 1H), 7.27 (t, 1H), 6.95-6.89 (m, 2H), 3.25-3.16 (m, 2H), 3.16-3.03(m, 2H), 1.95-1.78 (m, 6H).

Example 1

{5-[5-(5-Chloro-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3,4-thiadiazol-2-yl]-2H-tetrazol-2-yl}aceticacid

Step 1:5-(5-Chloro-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3,4-thiadiazole-2-carbonitrile.To a mixture of 5-bromo-1,3,4-thiadiazole-2-carbonitrile (200 mg, 1.053mmol), piperidine,5-chloro-3,4-dihydrospiro[chromene-2,4′-piperidine]hydrochloride salt(346 mg, 1.263 mmol) in dioxane (5 mL) was added DIPEA (0.551 mL, 3.16mmol). The mixture was stirred at room temperature for 2 h. Afterdilution with water, the mixture was extracted with EtOAc. The EtOAcextract was washed with 0.5M HCl (2×), brine, dried (Na₂SO₄) andconcentrated. Combi-Flash® (40 g, 20-50% EtOAc in hexanes for 20 min, 35mL/min, 18 mL/fraction) gave the title compound as yellow foam. ¹H NMR(500 MHz, acetone-d₆): δ 7.16 (t, 1H), 7.00 (d, 1H), 6.89 (d, 1H), 3.98(d, 2H), 3.78-3.71 (m, 2H), 2.83 (t, 2H), 2.02-1.89 (m, 6H).

Step 2:5-Chloro-1′-[5-(1H-tetrazol-5-yl)-1,3,4-thiadiazol-2-yl]-3,4-dihydrospiro[chromene-2,4′-piperidine].A mixture of5-(5-chloro-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3,4-thiadiazole-2-carbonitrile(340 mg, 0.980 mmol), ammonium chloride (157 mg, 2.94 mmol) and sodiumazide (127 mg, 1.961 mmol) in DMF (5 mL) was heated at 110° C. for 3 h.After cooling, the mixture was diluted with water, and acidified with 1NHCl (1 mL). The precipitate was collected, washed with water and driedto give the title compound as a white solid. MS: m/z 390 (MH+).

Step 3:Ethyl{5-[5-(5-chloro-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3,4-thiadiazol-2-yl]-2H-tetrazol-2-yl}acetate.A mixture of-chloro-1′-[5-(1H-tetrazol-5-yl)-1,3,4-thiadiazol-2-yl]-3,4-dihydrospiro[chromene-2,4′-piperidine](275 mg, 0.705 mmol), ethyl bromoacetate (120 μL, 1.078 mmol) andtriethylamine (250 μL, 1.794 mmol) in THF (10 mL) was refluxed for 3 h.After cooling, the mixture was diluted with water and extracted withEtOAc. The EtOAc extract was washed with water (2×), dried (Na₂SO₄) andconcentrated. Combi-Flash® (40 g, 20-60% EtOAc in hexanes for 20 min, 35mL/min, 20 mL/fraction) to give the less polarethyl{5-[5-(5-chloro-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3,4-thiadiazol-2-yl]-1H-tetrazol-1-yl}acetateas a white foam and the more polar title compound as a white foam. ¹HNMR (500 MHz, acetone-d₆): δ 7.16 (t, 1H), 7.01 (d, 1H), 6.90 (d, 1H),5.80 (s, 2H), 4.30 (q, 2H), 3.96 (d, 2H), 3.73-3.64 (m, 2H), 2.84 (m,2H), 2.03-1.90 (m, 6H), 1.26 (t, 3H).

Step 4:{5-[5-(5-Chloro-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3,4-thiadiazol-2-yl]-2H-tetrazol-2-yl}aceticacid A mixture ofethyl{5-[5-(5-chloro-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3,4-thiadiazol-2-yl]-2H-tetrazol-2-yl}acetate(200 mg, 0.420 mmol) and 1M NaOH (1 mL, 1.0 mmol) in THF (5 mL) and MeOH(1 mL) was stirred at room temperature for 2 h. The mixture was thendiluted with water and acidified with 1M HCl. White precipitate appearedand the mixture was extracted with EtOAc. The EtOAc extract was washedwith water, dried (Na₂SO₄) and concentrated. The resulting residue wasswished with Et₂O and a small amount of EtOAc, filtered and dried togive the title compound as a white powder. ¹H NMR (500 MHz, acetone-d₆):δ 7.16 (t, 1H), 7.00 (d, 1H), 6.90 (d, 1H), 5.79 (s, 2H), 3.96 (d, 2H),3.73-3.65 (m, 2H), 2.84 (t, 2H), 2.04-1.90 (m, 6H). MS: m/z 448 (MH+).

Example 2

{5-[3-(5-Chloro-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)isoxazol-5-yl]-2H-tetrazol-2-yl}aceticacid

Step 1: Ethyl 3-bromo-4,5-dihydroisoxazole-5-carboxylate. To avigorously stirred mixture of hydroxycarbonimidic dibromide (15.5 g,76.4 mmol) and ethyl acrylate (15.3 g, 153 mmol) in DMF (200 mL) wasadded a solution of 15 wt % aqueous KHCO₃ (102 mL, 153 mmol). Themixture was stirred at room temperature overnight. Water was added andthe mixture was extracted twice with methyl tert-butyl ether. Thecombined organic extracts were washed with brine, dried (Na₂SO₄) andconcentrated in vacuo to give the title compound.

Step 2: 3-Bromo-4,5-dihydroisoxazole-5-carboxamide. A mixture of ethyl3-bromo-4,5-dihydroisoxazole-5-carboxylate (6.2 g, 28 mmol) and asolution of 2 M ammonia in MeOH (56 mL) was stirred at room temperaturefor 1 to 2 hours. Volatile materials were removed in vacuo to give thecrude title compound as a white solid.

Step 3:3-(5-Chloro-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-4,5-dihydroisoxazole-5-carboxamide.A mixture of 3-bromo-4,5-dihydroisoxazole-5-carboxamide (500 mg, 2.59mmol), 5-chloro-3,4-dihydrospiro[chromene-2,4′-piperidine]hydrochloridesalt (800 mg, 2.92 mmol) and DIPEA (1.357 mL, 7.77 mmol) in ethanol (5mL) was refluxed for 6 h. After cooling, volatile materials were removedin vacuo. The resulting residue was diluted with water, acidified with1N HCl and extracted with EtOAc. The EtOAc extract was washedsucessively with 0.5M HCl, water (2×), dried (Na₂SO₄) and concentratedto give the title compound as a light brown powder.

Step 4:3-(5-Chloro-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)isoxazole-5-carboxamide.To a stirred suspension of3-(5-chloro-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-4,5-dihydroisoxazole-5-carboxamide(420 mg, 1.2 mmol) and sodium acetate (295 mg, 3.6 mmol) inchlorobenzene (5 mL) was added iodine (350 mg, 1.4 mmol). The mixturewas heated at reflux temperature for 3 h. After cooling, a solution ofNa₂S₂O₃, water and EtOAc were added. The mixture was stirred for 5 minand filtered through Celite™ to remove the insoluble material. Theorganic layer was then separated, washed with brine, dried (Na₂SO₄) andconcentrated. The resulting residue was triturated with Et₂O, filteredand dried to give the title compound as a light brown powder. MS: m/z348 (MH+).

Step 5:3-(5-Chloro-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)isoxazole-5-carbonitrile.To a suspension of3-(5-chloro-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)isoxazole-5-carboxamide(280 mg, 0.805 mmol) and TEA (0.337 mL, 2.415 mmol) in CH₂Cl₂ (8 mL) atroom temperature was added TFAA (0.171 mL, 1.208 mmol). The mixturebecame homogeneous almost immediately. After further stirring for 30min, the mixture was quenched with saturated NaHCO₃ and extracted withCH₂Cl₂. The CH₂Cl₂ extract was washed with brine, dried (Na₂SO₄) andconcentrated. Combi-Flash® (12 g, 20-50% EtOAc in hexanes for 20 min, 25mL/min, 20 mL/fraction) gave the title compound as a pale yellow oil,which solidifed on standing. ¹H NMR (500 MHz, acetone-d₆): δ 7.32 (d,1H), 7.15 (td, 1H), 6.99 (dd, 1H), 6.86 (dd, 1H), 3.65 (dd, 2H),3.44-3.34 (m, 2H), 2.83-2.79 (m, 2H), 2.01-1.79 (m, 6H). MS: m/z 330(MH+).

Step 6:{5-[3-(5-Chloro-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)isoxazol-5-yl]-2H-tetrazol-2-yl}aceticacid The title compound was prepared in a similar manner as describedfor Example 1, Steps 2 to 4 starting from3-(5-chloro-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)isoxazole-5-carbonitrile.¹H NMR (500 MHz, acetone-d₆): δ 7.15 (t, 1H), 7.01-6.96 (m, 2H), 6.88(d, 1H), 5.80 (s, 2H), 3.71 (m, 2H), 3.42-3.35 (m, 2H), 2.83 (m, 2H),1.97-1.81 (m, 6H). MS: m/z 431 (MH+).

Example 3

{5-[2-(5-Chloro-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3-thiazol-5-yl]-2H-tetrazol-2-yl}aceticacid

Step 1:tert-Butyl{5-[2-(5-chloro-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3-thiazol-5-yl]-2H-tetrazol-2-yl}acetate.To a solution oftert-butyl[5-(2-bromo-1,3-thiazol-5-yl)-2H-tetrazol-2-yl]acetate (80 mg,0.23 mmol) and5-chloro-3,4-dihydrospiro[chromene-2,4′-piperidinium]chloride (82 mg,0.30 mmol) in NMP (1.25 mL) was added DBU (91 μL, 0.60 mmol). The tubewas sealed and immersed into a preheated oil bath at 130° C., andstirred at this temperature for 20 min. The reaction was then dilutedwith EtOAc, poured into 0.5 N HCl, extracted with EtOAc, washed withwater (3×) and brine, dried (Na₂SO₄), filtered and concentrated. Afterevaporation of solvents, the residue was purified twice by flashchromatography on SiO₂ (10 g; gradient from 0 to 60% EtOAc/hexanes) toafford the title product as a white solid. LC-MS: m/z=503.1, 505.1(MH+). ¹H NMR (400 MHz, acetone-d₆): δ 7.85 (s, 1H), 7.17 (t, 1H), 7.01(dd, 1H), 6.91 (dd, 1H), 5.57 (s, 2H), 3.96 (dt, 2H), 3.61-3.53 (m, 2H),2.87-2.82 (m, 2H), 2.02-1.83 (m, 6H), 1.51 (s, 9H).

Step 2:{5-[2-(5-Chloro-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3-thiazol-5-yl]-2H-tetrazol-2-yl}aceticacid. Water (0.4 mL) and formic acid (1.6 mL, 42 mmol) were added totert-butyl{5-[2-(5-chloro-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3-thiazol-5-yl]-2H-tetrazol-2-yl}acetate(65 mg, 0.13 mmol) and the resulting solution was immersed into apreheated oil bath at 100° C. for 1 h. The reaction was poured intowater, extracted with EtOAc, washed with water (3×) and brine, dried(Na₂SO₄), filtered and concentrated. After evaporation of solvent, theresidue was dissolved into EtOAc and filtered through a pad of Celite™.The solvent was removed under vacuum and the resulting material wastriturated with Et₂O/heptane, filtered and dried to afford the titleproduct as a white solid. LC-MS: m/z=449.0, 447.0 (MH+). ¹H NMR (500MHz, DMSO-d₆): δ 13.77 (br s, 1H), 7.88 (s, 1H), 7.15 (t, 1H), 7.01 (d,1H), 6.86 (d, 1H), 5.69 (s, 2H), 3.86-3.78 (m, 2H), 3.53-3.43 (m, 2H),2.74 (t, 2H), 1.92 (t, 2H), 1.87-1.74 (m, 4H).

Example 4

{5-[2-(4-Oxo-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3-thiazol-5-yl]-2H-tetrazol-2-yl}aceticacid

Step 1:tert-Butyl{5-[2-(4-oxo-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3-thiazol-5-yl]-2H-tetrazol-2-yl}acetate.To a solution oftert-butyl[5-(2-bromo-1,3-thiazol-5-yl)-2H-tetrazol-2-yl]acetate (80 mg,0.23 mmol) and spiro[chromene-2,4′-piperidin]-4(3H)-one (68 mg, 0.31mmol) in NMP (1.25 mL) was added DBU (49 μL, 0.33 mmol). The tube wassealed and immersed into a preheated oil bath at 130° C., and stirred atthis temperature for 20 min. The reaction was diluted with EtOAc, pouredinto 0.5 N HCl, extracted with EtOAc, washed with water (3×) and brine,dried (Na₂SO₄), filtered and concentrated. After evaporation of thesolvent, the residue was purified by flash chromatography on SiO₂ (12 g;gradient from 0 to 60% EtOAc/hexanes) to afford the title product as apink solid. LC-MS: m/z=483.1 (MH+). ¹H NMR (400 MHz, acetone-d₆): δ7.85-7.82 (m, 2H), 7.63 (ddd, 1H), 7.17 (d, 1H), 7.13-7.08 (m, 1H), 5.58(s, 2H), 4.01-3.95 (m, 2H), 3.61 (td, 2H), 2.91 (s, 2H), 2.25-2.19 (m,2H), 2.03-1.92 (m, 2H), 1.51 (s, 9H).

Step 2:{5-[2-(4-Oxo-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3-thiazol-5-yl]-2H-tetrazol-2-yl}aceticacid. Water (0.4 mL) and formic acid (1.6 mL, 41.7 mmol) were added totert-butyl{5-[2-(4-oxo-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3-thiazol-5-yl]-2H-tetrazol-2-yl}acetate(54 mg, 0.112 mmol) and the resulting solution was immersed into apreheated oil bath at 100° C. for 1 h. The reaction was poured intowater, extracted with EtOAc, washed with water (3×) and brine, dried(Na₂SO₄), filtered and concentrated. The solvent was removed undervacuum and the resulting material was triturated with Et₂O/heptane,filtered and dried to afford the title product as a pink solid. LC-MS:m/z=427.1 (MH+). NMR (400 MHz, DMSO-d₆): δ 13.78 (br s, 1H), 7.88 (s,1H), 7.77 (dd, 1H), 7.64-7.59 (m, 1H), 7.15 (d, 1H), 7.09 (t, 1H), 5.69(s, 2H), 3.91-3.81 (m, 2H), 3.54-3.43 (m, 2H), 2.93 (s, 2H), 2.06 (d,2H), 1.94-1.84 (m, 2H).

Example 5

{5-[2-(2,3-Dihydro-1′H-spiro[indene-1,4′-piperidin]-1′-yl)-1,3-thiazol-5-yl]-2H-tetrazol-2-yl}aceticacid

Step 1:tert-Butyl{5-[2-(2,3-dihydro-1′H-spiro[indene-1,4′-piperidin]-1′-yl)-1,3-thiazol-5-yl]-2H-tetrazol-2-yl}acetateTo a solution oftert-butyl[5-(2-bromo-1,3-thiazol-5-yl)-2H-tetrazol-2-yl]acetate (80 mg,0.231 mmol) and 2,3-dihydrospiro[indene-1,4′-piperidinium]chloride (69.8mg, 0.312 mmol) in NMP (1.25 mL) was added DBU (87 μL, 0.577 mmol). Thetube was sealed and immersed into a preheated oil bath at 130° C., andstirred at this temperature for 20 min. The reaction was diluted withEtOAc, poured into 0.5 N HCl, extracted with EtOAc, washed with water(3×) and brine, dried (Na₂SO₄), filtered and concentrated. Afterevaporation of the solvents, the residue was purified by flashchromatography on SiO₂ (12 g) (gradient from 0 to 60% EtOAc/hexanes) toafford the title product as a white solid. LC-MS: m/z=453.2 (MH+).

Step 2:{5-[2-(2,3-Dihydro-1′H-spiro[indene-1,4′-piperidin]-1′-yl)-1,3-thiazol-5-yl]-2H-tetrazol-2-yl}aceticacid Water (0.4 mL) and formic acid (1.6 mL, 41.7 mmol) were added totert-butyl{5-[2-(2,3-dihydro-1′H-spiro[indene-1,4′-piperidin]-1′-yl)-1,3-thiazol-5-yl]-2H-tetrazol-2-yl}acetate(43 mg, 0.095 mmol) and the solution was immersed into a preheated oilbath at 100° C. for 1 h. The reaction was poured into water, extractedwith EtOAc, washed with water (3×) and brine, dried (Na₂SO₄), filteredand concentrated. Solvents were removed under vacuum and the materialwas triturated with Et₂O/heptane, filtered and dried to afford the titleproduct as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 13.78 (br s, 1H),7.90 (s, 1H), 7.27-7.22 (m, 2 H), 7.21-7.15 (m, 2H), 5.69 (s, 2H), 4.01(d, 2H), 3.42-3.35 (m, 2H), 2.92 (t, 2H), 2.13 (t, 2 H), 1.94 (td, 2H),1.62 (d, 2H). LC-MS: m/z=397.1 (MH+).

Example 6

{5-[2-(1′H-Spiro[1-benzofuran-3,4′-piperidin]-1′-yl)-1,3-thiazol-5-yl]-2H-tetrazol-2-yl}aceticacid

Step 1:tert-Butyl{5-[2-(1′H-spiro[1-benzofuran-3,4′-piperidin]-1′-yl)-1,3-thiazol-5-yl]-2H-tetrazol-2-yl}acetateTo a solution oftert-butyl[5-(2-bromo-1,3-thiazol-5-yl)-2H-tetrazol-2-yl]acetate (80 mg,0.231 mmol) and spiro[1-benzofuran-3,4′-piperidine] (74.3 mg, 0.393mmol) in NMP (1.25 mL) was added DBU (70 μL, 0.464 mmol). The tube wassealed and immersed into a preheated oil bath at 130° C., and stirred atthis temperature for 20 min. The reaction was diluted with EtOAc, pouredinto 0.5 N HCl, extracted with EtOAc, washed with water (3×) and brine,dried (Na₂SO₄), filtered and concentrated. After evaporation of thesolvents, the residue was purified by flash chromatography on SiO₂ (12g) (gradient 0 to 60% EtOAc/hexanes) to afford the title product as anoff-white solid. LC-MS: m/z=455.1 (MH+).

Step 2:{5-[2-(1′H-Spiro[1-benzofuran-3,4′-piperidin]-1′-yl)-1,3-thiazol-5-yl]-2H-tetrazol-2-yl}aceticacid Water (0.4 mL) and formic acid (1.6 mL, 41.7 mmol) were added totert-butyl{5-[2-(1′H-spiro[1-benzofuran-3,4′-piperidin]-1′-yl)-1,3-thiazol-5-yl]-2H-tetrazol-2-yl}acetate(57 mg, 0.125 mmol) and the solution was immersed into a preheated oilbath at 100° C. for 1 h. The reaction was poured into water, extractedwith EtOAc, washed with water (3×) and brine, dried (Na₂SO₄), filteredand concentrated. Solvents were removed under vacuum and the materialwas triturated with Et₂O/heptane, filtered and dried to afford the titleproduct as a white solid. LC-MS: m/z=399.1 (MH+). NMR (400 MHz,DMSO-d₆): δ 13.79 (br s, 1H), 7.90 (s, 1H), 7.30 (d, 1H), 7.15 (t, 1H),6.87 (t, 1H), 6.82 (d, 1H), 5.70 (s, 2H), 4.52 (s, 2H), 4.00 (d, 2H),3.39-3.28 (m, 2H), 2.01 (td, 2H), 1.81 (d, 2H).

Example 7

{5-[2-(1′H-Spiro[indene-1,4′-piperidin]-1′-yl)-1,3-thiazol-5-yl]-2H-tetrazol-2-yl}aceticacid

Step 1:tert-Butyl{5-[2-(1′H-spiro[indene-1,4′-piperidin]-1′-yl)-1,3-thiazol-5-yl]-2H-tetrazol-2-yl}acetateTo a solution oftert-butyl[5-(2-bromo-1,3-thiazol-5-yl)-2H-tetrazol-2-yl]acetate (80 mg,0.231 mmol) and spiro[indene-1,4′-piperidinium]chloride (87 mg, 0.393mmol) in NMP (1.25 mL) was added DBU (87 μL, 0.577 mmol). The tube wassealed and immersed into a preheated oil bath at 130° C., and stirred atthis temperature for 20 min. The reaction was diluted with EtOAc, pouredinto 0.5 N HCl, extracted with EtOAc, washed with water (3×) and brine,dried (Na₂SO₄), filtered and concentrated. After evaporation of thesolvents, the residue was purified by flash chromatography on SiO₂ (12g) (gradient 0 to 60% EtOAc/hexanes) to afford the title product as awhite solid. LC-MS: m/z=451.1 (MH+).

Step 2:{5-[2-(1′H-Spiro[indene-1,4′-piperidin]-1′-yl)-1,3-thiazol-5-yl]-2H-tetrazol-2-yl}aceticacid Water (0.4 mL) and formic acid (1.6 mL, 41.7 mmol) were added totert-butyl{5-[2-(1′H-spiro[indene-1,4′-piperidin]-1′-yl)-1,3-thiazol-5-yl]-2H-tetrazol-2-yl}acetate(61 mg, 0.135 mmol) and the solution was immersed into a preheated oilbath at 100° C. for 1 h. The reaction was poured into water, extractedwith EtOAc, washed with water (3×) and brine, dried (Na₂SO₄), filteredand concentrated. Solvents were removed under vacuum and the materialwas triturated with Et₂O/heptane, filtered and dried to afford the titleproduct as a white solid. LC-MS: m/z=395.0 (MH+). ¹H NMR (400 MHz,DMSO-d₆): δ 13.80 (br s, 1H), 7.93 (s, 1H), 7.50 (d, 1H), 7.38 (d, 1H),7.26 (t, 1H), 7.23-7.17 (m, 2H), 6.89 (d, 1H), 5.71 (s, 2H), 4.12 (d,2H), 3.57 (td, 2H), 2.23 (td, 2H), 1.35 (d, 2H).

Example 8

{5-[5-(4-Oxo-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3,4-thiadiazol-2-yl]-2H-tetrazol-2-yl}aceticacid

Step 1:tert-Butyl{5-[5-(4-oxo-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3,4-thiadiazol-2-yl]-2H-tetrazol-2-yl}acetateThe title compound was prepared in a similar manner as that describedfor Example 5 (step 1) fromtert-butyl[5-(2-bromo-1,3-thiazol-5-yl)-2H-tetrazol-2-yl]acetate andspiro[chromene-2,4′-piperidin]-4(3H)-one hydrochloride.

Step 2:{5-[5-(4-Oxo-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3,4-thiadiazol-2-yl]-2H-tetrazol-2-yl}aceticacid. To a solution oftert-butyl{5-[5-(4-oxo-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3,4-thiadiazol-2-yl]-2H-tetrazol-2-yl}acetate(30 mg, 0.062 mmol) in dichloromethane (0.5 mL) was added TFA (200 uL).The reaction was stirred at room temperature overnight. The reactionmixture was co-evaporated several times with CH₂Cl₂, ether and hexanesuntil residue became solid. The residue was purified by trituration inether/hexanes (1:10) to afford the title compound as a solid. ¹H NMR(500 MHz, DMSO-d₆): δ 7.78-7.75 (m, 1H), 7.62 (d, 1H), 7.16-7.12 (m,1H), 7.11-7.07 (m, 1H), 5.83 (s, 2H), 3.89-3.84 (m, 2H), 3.65-3.57 (m,2H), 2.92 (s, 2H), 2.11-2.03 (m, 2H), 1.96-1.89 (m, 2H). MS (+ESI): m/z428 (MH⁺).

Example 9

{5-[2-(4-Oxo-3,4-dihydro-1′H-spiro[1,3-benzoxazine-2,4′-piperidin]-1′-yl)-1,3-thiazol-5-yl]-2H-tetrazol-2-yl}aceticacid

Step 1:tert-Butyl{5-[2-(4-oxo-3,4-dihydro-1′H-spiro[1,3-benzoxazine-2,4′-piperidin]-1′-yl)-1,3-thiazol-5-yl]-2H-tetrazol-2-yl}acetateThe title compound was prepared in a similar manner as that describedfor Example 5 (step 1) fromtert-butyl[5-(2-bromo-1,3-thiazol-5-yl)-2H-tetrazol-2-yl]acetate andspiro[1,3-benzoxazine-2,4′-piperidin]-4(3H)-one.

Step 2:2-Methoxyethyl{[5-(5-chloro-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)[1,3]thiazolo[5,4-d]pyrimidin-2-yl]amino}acetateThe title compound was prepared fromtert-butyl{5-[2-(4-oxo-3,4-dihydro-1′H-spiro[1,3-benzoxazine-2,4′-piperidin]-1′-yl)-1,3-thiazol-5-yl]-2H-tetrazol-2-yl}acetateand LiOH in THF—H₂O at 0° C. HOAc was used to acidify in the work-up. ¹HNMR (500 MHz, acetone-d₆): δ 7.88 (d, 1H), 7.82 (s, 1H), 7.58 (t, 1H),7.19-7.13 (m, 2H), 5.38 (s, 2H), 4.03 (d, 2H), 3.58 (t, 2H), 2.34 (d,2H), 2.15-2.05 (m, 2H). MS (+ESI): m/z 428 (MH⁺).

Example 10

{5-[5-(1-Oxo-1,4-dihydro-1′H-spiro[isochromene-3,4′-piperidin]-1′-yl)-1,3,4-thiadiazol-2-yl]-2H-tetrazol-2-yl}aceticacid

Step 1:tert-Butyl{5-[5-(1-oxo-1,4-dihydro-1′H-spiro[isochromene-3,4′-piperidin]-1′-yl)-1,3,4-thiadiazol-2-yl]-2H-tetrazol-2-yl}acetateThe title compound was prepared in a similar manner as that describedfor Example 5 (step 1) fromtert-butyl[5-(2-bromo-1,3-thiazol-5-yl)-2H-tetrazol-2-yl]acetate andspiro[isochromene-3,4′-piperidin]-1(4H)-one hydrochloride.

Step 2:{5-[5-(1-Oxo-1,4-dihydro-1′H-spiro[isochromene-3,4′-piperidin]-1′-yl)-1,3,4-thiadiazol-2-yl]-2H-tetrazol-2-yl}aceticacid The title compound was prepared in a similar manner as thatdescribed for Example 8 (step 2) fromtert-butyl{5-[5-(1-oxo-1,4-dihydro-1′H-spiro[isochromene-3,4′-piperidin]-1′-yl)-1,3,4-thiadiazol-2-yl]-2H-tetrazol-2-yl}acetateand TFA. ¹H NMR (500 MHz, DMSO-d₆): δ 7.97-7.94 (m, 1H), 7.70-7.66 (m,1H), 7.49-7.45 (m, 1H), 7.41-7.38 (m, 1H), 5.83 (s, 2H), 3.88-3.82 (m,2H), 3.62-3.57 (m, 2H), 3.23 (s, 2H), 2.03-1.89 (m, 4H). MS (+ESI): m/z428 (MH⁺).

Example 11

{5-[5-(5-Methoxy-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3,4-thiadiazol-2-yl]-2H-tetrazol-2-yl}aceticacid

Step 1: Benzyl5-methoxy-4-oxo-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidine]-1′-carboxylate.To a solution of benzyl 4-oxopiperidine-1-carboxylate (2.354 g, 10.09mmol) in methanol (21 ml), freshly distilled pyrrolidine (1.2 ml, 14.51mmol) followed by 1-(2-hydroxy-6-methoxyphenyl)ethanone (1.92 g, 11.55mmol) was added and the mixture stirred under external temperature of+73° C. for 90 min, cooled down to room temperature, diluted with EtOAcand successively washed with aqueous 5% KHSO₄, 2M NaOH in water andwater, dried over MgSO₄, filtered and concentrated. The oily residue wassubmitted to chromatographic column of silicagel eluted with 30% to 90%EtOAc in hexane to give the title product as white foam. MS: m/z=382.2(MH+). ¹H NMR (500 MHz, DMSO-d₆): δ 7.49 (t, 1H), 7.36 (m, 5H), 6.65 (t,2H), 5.10 (s, 2H), 3.8 (m, overlapped with singulet at 3.79 ppm); 3.79(s, 3H); 3.22 (bs, 2H), 2.72 (bs, 2H); 1.85 (d, 2H); 1.63 (m, 2H).

Step 2:Benzyl-4-hydroxy-5-methoxy-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidine]-1′-carboxylate.A solution of benzyl5-methoxy-4-oxo-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidine]-1′-carboxylate(629.5 mg, 1.650 mmol) in THF (1.5 ml) and MeOH (3.00 ml) stirred at 0°C., was treated with solid sodium borohydride (190 mg, 5.02 mmol) slowlyadded portion wise. After the addition was completed, the final mixturewas further stirred at the same temperature for 2 h, quenched at 0° C.by addition of acetone, diluted with EtOAc. The mixture was washed withsaturated NaHCO₃, dried over Na₂SO₄, filtered and concentrated to givethe title compound as a beige solid, which was used in the next stepwithout further purification. MS: m/z=406.2 (MNa+).

Step 3: 5-methoxy-3,4-dihydrospiro[chromene-2,4′-piperidine] A degassedsolution ofbenzyl4-hydroxy-5-methoxy-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidine]-1′-carboxylate(576 mg, 1.502 mmol) in ethyl acetate (25 ml) was treated with solid 10%Pd on carbon (223 mg, 14 mol %), and then MeOH (150 ml) was added. Afterstirring under vacuum for 3 min, a balloon filled with H₂ was adaptedand the final suspension stirred at room temperature for 6 h. Then 10 MHCl was added (3 mL) and stirring continued under H₂ overnight. Thereaction was filtered through a pad of Celite™ and concentrated, thendiluted with dichloromethane, washed with 2M NaOH in brine, dried overMgSO₄, filtered and concentrated to give the title compound as acolorless oil. MS: m/z=234.2 (MH+). ¹H NMR (500 MHz, DMSO-d₆): δ 7.02(t, 1H), 6.45 (d, 1H), 6.37 (d, 1H), 4.10 (bs, 1H), 3.75 (s, 3H); 2.70(m, 2H), 2.54 (m, overlapped with signal of solvent); 2.65 (m, 2H), 1.72(t, 2H), 1.58 (m, 2H), 1.46 (m, 2H).

Step 4:Ethyl{5-[5-(5-methoxy-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3,4-thiadiazol-2-yl]-2H-tetrazol-2-yl}acetate.A mixture of 5-methoxy-3,4-dihydrospiro[chromene-2,4′-piperidine] (201mg, 1.0 mmol),ethyl[5-(5-bromo-1,3,4-thiadiazol-2-yl)-2H-tetrazol-2-yl]acetate (322mg, 1.009 mmol) and K₂CO₃ (438 mg, 3.17 mmol) was suspended in dry DME(7 mL), the containing vial sealed and the mixture stirred under N₂ atexternal temperature of +80° C. for 80 minutes. The reaction was dilutedwith EtOAc, and washed with saturated NaHCO₃, then water, dried overMgSO₄, filtered and concentrated. The resulting brown oily residue wassubmitted to chromatographic column of silica gel and eluted with 40% to80% EtOAc in hexane to give the title compound as a yellow foam. MS:m/z=472.2 (MH+). ¹H NMR (500 MHz, DMSO-d₆): δ 7.08 (t, 1H), 6.52 (d,1H), 6.48 (d, 1H), 5.95 (s, 2H), 4.24 (q, 2H), 3.84 (m, 2H); 3.77 (s,3H); 3.57 (m, 2H); 2.58 (m, 2H), 1.85-1.75 (m, 6H), 1.25 (t, 3H).

Step 5:{5-[5-(5-Methoxy-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3,4-thiadiazol-2-yl]-2H-tetrazol-2-yl}aceticacid. A solution ofethyl{5-[5-(5-methoxy-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3,4-thiadiazol-2-yl]-2H-tetrazol-2-yl}acetate(220 mg, 0.467 mmol) in THF (8 mL) and ethanol (3 mL), was treated witha solution of NaOH (303 mg, 7.58 mmol) in water (4.0 mL). The resultingsuspension stirred at room temperature for 1.5 h, and then diluted withDCM, washed with a 5% KHSO₄ in water (final pH=1.5), dried over MgSO₄,filtered and concentrated. The resulting residue was triturated withEt₂O, filtered and stored under vacuum to the title compound as a paleyellow solid. MS: m/z=444.1 (MH+). ¹H NMR (500 MHz, DMSO-d₆): δ 13.9(bs, 1H); 7.05 (t, 1H), 6.52 (d, 1H), 6.48 (d, 1H), 5.80 (s, 2H), 3.85(m, 2H); 3.76 (s, 3H); 3.55 (m, 2H); 2.58 (m, 2H), 1.85-1.75 (m, 6H).

Example 12

{5-[5-(5-Hydroxy-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3,4-thiadiazol-2-yl]-2H-tetrazol-2-yl}aceticacid The title compound was prepared through 5 synthetic steps in thesame manner as described for example 13, but using1-(2,6-dihydroxyphenyl)ethanone instead1-(2-hydroxy-6-methoxyphenyl)ethanone in the step 1 the give the titlecompound as a white solid. MS: m/z=430.1 (MH+). ¹H NMR (500 MHz,DMSO-d₆): δ 13.9 (bs, 1H); 9.40 (s, 1H); 6.90 (t, 1H), 6.38 (d, 1H),6.30 (d, 1H), 5.80 (s, 2H), 3.85 (d, 2H); 3.56 (t, 2H); 2.55 (m, 2H,partially overlapped with signal of solvent), 1.85-1.75 (m, 6H).

Example 13

{5-[5-(5-Chloro-4-oxo-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3,4-thiadiazol-2-yl]-2H-tetrazol-2-yl}aceticacid

Step 1:Ethyl{5-[5-(5-chloro-4-oxo-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3,4-thiadiazol-2-yl]-2H-tetrazol-2-yl}acetate.To a solution of Intermediate 5 (100 mg, 0.313 mmol) and5-chlorospiro[chromene-2,4′-piperidin]-4(3H)-one hydrochloride (99 mg,0.345 mmol) in THF (1.6 mL) was added TEA (131 μl, 0.94 mmol). Thereaction mixture was warmed to 80° C. for 24 h. The solvent wasevaporated under reduced pressure and the residue was purified byCombiflash™, eluting with a gradient of 40-80% EtOAc/hexanes to affordthe title compound.

Step 2:{5-[5-(5-Chloro-4-oxo-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3,4-thiadiazol-2-yl]-2H-tetrazol-2-yl}aceticacid. The title compound was prepared in a similar manner as thatdescribed for Example 9 Step 2 fromethyl{5-[5-(5-chloro-4-oxo-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3,4-thiadiazol-2-yl]-2H-tetrazol-2-yl}acetateand LiOH at 0° C. ¹H NMR (500 MHz, DMSO-d₆): δ 7.53 (t, 1H), 7.14-7.11(m, 2H), 5.81 (s, 2H), 3.89 (d, 2H), 5.61 (t, 2H), 2.99 (s, 2H), 2.19(d, 2H), 1.95 (d, 2H). MS (+ESI): m/z 463 (MH⁺).

Example 14

{5-[2-(5-Chloro-4-oxo-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3-thiazol-5-yl]-2H-tetrazol-2-yl}aceticacid

Step 1:tert-Butyl{5-[2-(5-chloro-4-oxo-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3-thiazol-5-yl]-2H-tetrazol-2-yl}acetate.The title compound was prepared in a similar manner as that describedfor Example 5 Step 1 from Intermediate 3 and5-chlorospiro[chromene-2,4′-piperidin]-4(3H)-one hydrochloride.

Step 2:{5-[2-(5-Chloro-4-oxo-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3-thiazol-5-yl]-2H-tetrazol-2-yl}aceticacid The title compound was prepared in a similar manner as thatdescribed for Example 9 Step 2 fromtert-butyl{5-[2-(5-chloro-4-oxo-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3-thiazol-5-yl]-2H-tetrazol-2-yl}acetateand LiOH at 0° C. ¹H NMR (400 MHz, DMSO-d₆): δ 7.90 (s, 1H), 7.57 (t,1H), 7.18-7.11 (m, 2H), 5.71 (s, 2H), 3.85 (d, 2H), 3.49 (t, 2H), 2.95(s, 2H), 2.03 (d, 2H), 1.89 (t, 2H). MS (+ESI): m/z 462 (MH⁺).

Example 15

{5-[3-(5-Chloro-4-oxo-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)isoxazol-5-yl]-2H-tetrazol-2-yl}aceticacid

Step 1:tert-Butyl{5-[3-(5-chloro-4-oxo-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-4,5-dihydroisoxazol-5-yl]-2H-tetrazol-2-yl}acetate.To a solution of tert-butyl[5-(3-bromo-4,5-dihydroisoxazol-5-yl)-2Htetrazol-2-yl]acetate (200 mg, 0.602 mmol) and5-chlorospiro[chromene-2,4′-piperidin]-4(3H)-one hydrochloride (191 mg,0.662 mmol) in dry t-BuOH (3.01 mL) was added sodium bicarbonate (152mg, 1.81 mmol). The mixture was warmed to 115° C. for 24 h. The reactionmixture was diluted with water (50 mL) and extracted with EtOAc (3×20mL). The combined organic layers were dried (MgSO₄), filtered andevaporated under reduced pressure. The residue was purified byCombiflash™, eluting with a gradient of 20-70% EtOAc/Hexanes to affordthe title compound.

Step 2:tert-Butyl{5-[3-(5-chloro-4-oxo-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)isoxazol-5-yl]-2H-tetrazol-2-yl}acetate.To a solution oftert-butyl{5-[3-(5-chloro-4-oxo-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-4,5-dihydroisoxazol-5-yl]-2H-tetrazol-2-yl}acetate(52 mg, 0.103 mmol) in THF (2.1 mL) was added portion wise (3×) CAN (113mg, 0.207 mmol) over 45 minutes. 15 minutes later, the reaction mixturewas diluted with water (20 mL) extracted with EtOAc (3×10 mL). Thecombined organic layers were dried (MgSO₄), filtered and evaporatedunder reduced pressure. The resulting residue was purified byCombiflash™, eluting with a gradient of 20-70% EtOAc/Hexanes to affordthe title compound.

Step 3:{5-[3-(5-Chloro-4-oxo-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)isoxazol-5-yl]-2H-tetrazol-2-yl}aceticacid The title compound was prepared in a similar manner as thatdescribed for Example 8 Step 2 fromtert-butyl{5-[3-(5-chloro-4-oxo-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)isoxazol-5-yl]-2H-tetrazol-2-yl}acetateand TFA. ¹H NMR (500 MHz, DMSO-d₆): δ 7.52 (t, 1H), 7.25 (s, 1H), 7.11(d, 2H), 5.83 (s, 2H), 3.67 (d, 2 H), 3.29 (t, 2H), 2.92 (s, 2H), 1.97(d, 2H), 185 (t, 2H). MS (+ESI): m/z 446 (MH⁺).

Example 16

(5-{3-[5-(Trifluoromethoxy)-3,4-dihydro-1H-spiro[chromene-2,4′-piperidin]-1′-yl]isoxazol-5-yl}-2H-tetrazol-2-yl)aceticacid

Step 1: tert-Butyl(5-{3-[5-(trifluoromethoxy)-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl]-4,5-dihydroisoxazol-5-yl}-2H-tetrazol-2-yl)acetateA suspension of dried Na₂CO₃ (694 mg, 6.55 mmol) in anhydrous t-BuOH wasadded5-(trifluoromethoxy)-3,4-dihydrospiro[chromene-2,4′-piperidinium]chloride(848 mg, 2.62 mmol) (Intermediate 8) andtert-butyl[5-(3-bromo-4,5-dihydroisoxazol-5-yl)-2H-tetrazol-2-yl]acetate(725 mg, 2.183 mmol) (Intermediate 7). The mixture was directly heatedto 115° C. for 24 h. The reaction mixture was diluted with MTBE, pouredinto aq. NH₄Cl and extracted with EtOAc. The organic layer was washedwith water and brine. The aqueous phases were back extracted with EtOAc.The combined organic layers were dried (MgSO₄), filtered and evaporatedunder reduced pressure. The residue was purified by columnchromatography on SiO₂ (50 g, gradient from 0 to 70% EtOAc/hexanes) toafford the title compound as a white solid. LC-MS: m/z=539.1 (MH+).

Step 2: tert-Butyl(5-{3-[5-(trifluoromethoxy)-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl]isoxazol-5-yl}-2H-tetrazol-2-yl)acetateTo tert-butyl(5-{3-[5-(trifluoromethoxy)-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl]-4,5-dihydroisoxazol-5-yl}-2H-tetrazol-2-yl)acetate (880 mg, 1.634 mmol) in THF (10mL) was added in one portion CAN (1344 mg, 2.451 mmol) at −78° C. Thereaction was slowly warmed to 0° C. for 40 min. Then the reactionmixture was cooled to −78° C., diluted with water, and extracted withEtOAc. The organic layer was washed with brine. The aqueous phases wereback extracted with EtOAc. The combined organic layers were dried(MgSO₄), filtered and evaporated under reduced pressure. The resultingresidue was purified by column chromatography on SiO₂ (50 g, gradientfrom 0 to 50% EtOAc/hexanes) to afford the title compound as a whitesolid. LC-MS: m/z=537.1 (MH+).

Step 3:(5-{3-[5-(Trifluoromethoxy)-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl]isoxazol-5-yl}-2H-tetrazol-2-yl)aceticacid Water (0.8 mL) and formic acid (3.2 mL, 83 mmol) were added totert-butyl(5-{3-[5-(trifluoromethoxy)-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl]isoxazol-5-yl}-2H-tetrazol-2-yl)acetate(378 mg, 0.705 mmol) and the final solution was immersed into apreheated oil bath at 100° C. for 30 min. The reaction was poured intowater and extracted with EtOAc. The organic layer was washed with water(5×) and brine, dried (Na₂SO₄), filtered and concentrated. The resultingresidue was triturated with Et₂O/heptane, filtered and dried to affordthe title compound as a white solid. LC-MS: m/z=481.1 (MH+). ¹H NMR (400MHz, DMSO-d₆): δ 13.92 (br s, 1H), 7.28-7.20 (m, 2H), 6.93-6.88 (m, 2H),5.85 (s, 2H), 3.69-3.59 (m, 2H), 3.33-3.27 (m, 2H), 2.74 (t, 2H), 1.88(t, 2H), 1.86-1.70 (m, 4H).

Example 17

(5-{5-[5-(Trifluoromethoxy)-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl]-1,3,4-thiadiazol-2-yl}-2H-tetrazol-2-yl)aceticacid

Step 1: tert-Butyl(5-{5-[5-(trifluoromethoxy)-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl]-1,3,4-thiadiazol-2-yl}-2H-tetrazol-2-yl)acetateA solution oftert-butyl[5-(5-bromo-1,3,4-thiadiazol-2-yl)-2H-tetrazol-2-yl]acetate(10.5 g, 30.2 mmol; Intermediate 6) and5-(trifluoromethoxy)-3,4-dihydrospiro[chromene-2,4′-piperidinium]chloride(10.77 g, 33.3 mmol; Intermediate 8) in THF (30 mL) was treated withHunig's base (15.85 mL, 91 mmol). The reaction mixture was heated to 80°C. for 6 h. Then the reaction was diluted with EtOAc, poured into 0.5 NHCl, and extracted with EtOAc. The organic layer was separated, washedwith water (2×) and brine, dried (Na₂SO₄), filtered and concentrated.After evaporation of the solvents, the resulting residue was purified byflash chromatography on SiO₂ (gradient 0 to 30% MTBE/toluene) followedby multiple recrystallizations from toluene to afford the title compoundas a white solid. LC-MS: m/z=554.1 (MH+). ¹H NMR (400 MHz, acetone-d₆):δ 7.28 (t, 1H), 6.97 (d, 1H), 6.92 (d, 1H), 5.70 (s, 2H), 4.04-3.95 (m,2H), 3.77-3.67 (m, 2H), 2.89-2.84 (m, 2 H), 2.05-1.91 (m, 6H), 1.52 (s,9H).

Step 2:(5-{5-[5-(Trifluoromethoxy)-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl]-1,3,4-thiadiazol-2-yl}-2H-tetrazol-2-yl)aceticacid Water (13 mL) and formic acid (52 mL, 1356 mmol) were added totert-butyl(5-{5-[5-(trifluoromethoxy)-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl]-1,3,4-thiadiazol-2-yl}-2H-tetrazol-2-yl)acetate(12.0 g, 21.68 mmol) and the final suspension was heated to 100° C. for30 min. The reaction was poured into water (400 mL), extracted withEtOAc (300 mL), washed with water (4×400 mL) and brine (400 mL). Theaqueous phases were back-extracted with EtOAc (300 mL). The organiclayers were combined, dried (MgSO₄), filtered and concentrated. Afterevaporation of the solvents and co-evaporation with Et₂O/heptane, theresidue was triturated with 5% Et₂O in pentane (400 mL) overnight,filtered and dried to give the title compound as a white solid. LC-MS:m/z=498.0 (MH+). ¹H NMR (400 MHz, DMSO-d₆): δ 13.90 (br s, 1H), 7.26 (t,1H), 6.96-6.88 (m, 2H), 5.84 (s, 2H), 3.92-3.82 (m, 2H), 3.66-3.55 (m,2H), 2.75 (t, 2H), 1.95-1.81 (m, 6H).

Example 18

(5-{2-[5-(Trifluoromethoxy)-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl]-1,3-thiazol-5-yl}-2H-tetrazol-2-yl)aceticacid

Step 1: tert-Butyl(5-{2-[5-(trifluoromethoxy)-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl]-1,3-thiazol-5-yl}-2H-tetrazol-2-yl)acetateA solution oftert-butyl[5-(5-bromo-1,3-thiazol-2-yl)-2H-tetrazol-2-yl]acetate (7.5 g,21.7 mmol; Intermediate 3) and5-(trifluoromethoxy)-3,4-dihydrospiro[chromene-2,4′-piperidinium]chloride(7.71 g, 23.8 mmol; Intermediate 8) in THF (20 mL) was treated withHunig's base (11.4 mL, 65.0 mmol). The reaction was heated to 80° C. andstirred at this temperature under reflux overnight, then the reactionwas diluted with EtOAc, and poured into 0.5 N HCl. The resulting mixturewas extracted with EtOAc, washed with 0.5 N HCl (2×) and brine, dried(MgSO₄), filtered and concentrated. After evaporation of the solvents,the resulting residue was purified by flash chromatography on SiO₂(gradient 0 to 30% EtOAc/toluene) followed by multiple successiverecrystallizations from toluene/heptane (1:1) with cooling to 0° C. toafford the title compound as a white solid. LC-MS: m/z=553.1 (MH+). ¹HNMR (400 MHz, acetone-d₆): δ 7.86 (s, 1H), 7.27 (t, 1H), 6.96 (d, 1H),6.91 (d, 1H), 5.57 (s, 2H), 4.01-3.91 (m, 2H), 3.65-3.53 (m, 2H),2.89-2.82 (m, 2H), 2.02-1.84 (m, 6H), 1.51 (s, 9H).

Step 2:(5-{2-[5-(Trifluoromethoxy)-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl]-1,3-thiazol-5-yl}-2H-tetrazol-2-yl)aceticacid Water (7.6 mL) and formic acid (30 mL, 782 mmol) were added totert-butyl(5-{2-[5-(trifluoromethoxy)-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl]-1,3-thiazol-5-yl}-2H-tetrazol-2-yl)acetate(7.80 g, 14.1 mmol) and the final solution was heated to 100° C. for 2h. The reaction was poured into water (400 mL), extracted with EtOAc(300 mL), washed with water (4×400 mL) and brine (400 mL). The aqueousphases were back-extracted with EtOAc (300 mL) and the organic layerswere combined, dried (MgSO₄), filtered and concentrated. Afterevaporation of the solvents, the resulting residue was co-evaporatedwith toluene (100 mL) and dried under vacuum to give the title compound.LC-MS: m/z=497 (MH⁺). ¹H NMR (500 MHz, DMSO-d₆): δ 13.77 (br s, 1H),7.88 (s, 1H), 7.24 (t, 1H), 6.93-6.87 (m, 2H), 5.67 (s, 2H), 3.88-3.80(m, 2H), 3.54-3.44 (m, 2H), 2.74 (t, 2H), 1.92-1.76 (m, 6H).

Example 19

(5-{5-[4-Oxo-5-(trifluoromethoxy)-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl]-1,3,4-thiadiazol-2-yl}-2H-tetrazol-2-yl)aceticacid The title compound was prepared, as a white solid, through twosynthetic steps in the same manner as described for Example 17, butusing4-oxo-5-(trifluoromethoxy)-3,4-dihydrospiro[chromene-2,4′-piperidinium]chloride(Intermediate 9) in step 1. LC-MS: m/z=512 (MH⁺). ¹H NMR (400 MHz,acetone-d₆): δ 7.70 (t, 1H), 7.27 (dd, 1 H), 7.04 (d, 1H), 5.70 (s, 2H),4.04-3.97 (m, 2H), 3.79-3.68 (m, 2H), 2.97 (s, 2H), 2.25 (d, 2 H),2.14-2.04 (m, 2H).

Example 20

(5-{5-[4-Hydroxy-5-(trifluoromethoxy)-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl]-1,3,4-thiadiazol-2-yl}-2H-tetrazol-2-yl)aceticacid A suspension of(5-{5-[4-oxo-5-(trifluoromethoxy)-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl]-1,3,4-thiadiazol-2-yl}-2H-tetrazol-2-yl)aceticacid (146 mg, 0.285 mmol; Example 19) in THF (3 mL) and MeOH (3 mL) wastreated with NaBH₄ (86 mg, 2.284 mmol) at −78° C. The suspension waswarmed to 0° C. and stirred for 30 min. The suspension was then cooledto −78° C. and acetone was added to quench the excess of hydride beforeto be warmed to 0° C. The reaction mixture was poured into 10% aqueousAcOH and the aqueous media was extracted with EtOAc. The organic layerwas washed with water (2×), and brine, dried (MgSO₄), filtered andconcentrated. The resulting residue was triturated with Et₂O/heptane,filtered and dried to give the title compound as a white solid. LC-MS:m/z=514 (MH⁺). ¹H NMR (400 MHz, acetone-d₆): δ 7.36 (t, 1H), 6.98 (d,1H), 6.97-6.93 (m, 1H), 5.53 (s, 2H), 5.12 (dd, 1H), 4.03-3.97 (m, 1H),3.91-3.79 (m, 2H), 3.64-3.57 (m, 1H), 2.54-2.48 (m, 1H), 2.30 (dd, 1H),2.12-2.06 (m, 4H).

Example 21

(5-{2-[4-Oxo-5-(trifluoromethoxy)-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl]-1,3-thiazol-5-yl}-2H-tetrazol-2-yl)aceticacid

Step 1: tert-Butyl(5-{2-[4-oxo-5-(trifluoromethoxy)-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl]-1,3-thiazol-5-yl}-2H-tetrazol-2-yl)acetateTo a solution oftert-butyl[5-(2-bromo-1,3-thiazol-5-yl)-2H-tetrazol-2-yl]acetate (308mg, 0.888 mmol) (Intermediate 2) and4-oxo-5-(trifluoromethoxy)-3,4-dihydrospiro[chromene-2,4′-piperidinium]chloride(250 mg, 0.740 mmol; Intermediate 9) in NMP (1 mL) was added DBU (0.223mL, 1.48 mmol). The tube was sealed and immersed into a preheated oilbath at 130° C., and stirred at this temperature for 20-30 min. Thereaction was diluted with EtOAc, poured into 0.5 N HCl, extracted withEtOAc, washed with water (3×) and brine, dried (MgSO4), filtered andconcentrated. After evaporation of the solvents, the resulting residuewas purified by flash chromatography on SiO₂ (24 g, gradient 0 to 70%EtOAc/hexanes) to give the title compound as a foamy yellow solid.LC-MS: m/z=567.1 (MH⁺).

Step 2:(5-{2-[4-Oxo-5-(trifluoromethoxy)-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl]-1,3-thiazol-5-yl}-2H-tetrazol-2-yl)aceticacid Water (0.4 mL) and formic acid (1.6 mL, 41.7 mmol) were added totert-butyl(5-{2-[4-oxo-5-(trifluoromethoxy)-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl]-1,3-thiazol-5-yl}-2H-tetrazol-2-yl)acetate(328 mg, 0.579 mmol) and the final solution was immersed into apreheated oil bath at 100° C. for 45 min. The reaction was poured intowater, extracted with EtOAc, washed with water (3×) and brine, dried(MgSO₄), filtered and concentrated. After evaporation of the solvents,the resulting material was triturated with Et₂O/heptane, filtered anddried to give the title compound as an off-white solid. LC-MS: m/z=511(MH⁺). ¹H NMR (500 MHz, DMSO-d₆): δ 13.74 (br s, 1H), 7.88 (s, 1H), 7.68(t, 1H), 7.23 (d, 1H), 7.04 (d, 1H), 5.68 (s, 2H), 3.89-3.83 (m, 2H),3.52-3.45 (m, 2H), 2.95 (s, 2H), 2.05 (d, 2H), 1.94-1.89 (m, 2H).

Example 22

{5-[3-(5-Bromo-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)isoxazol-5-yl]-2H-tetrazol-2-yl}aceticacid The title compound was prepared, as a white solid, through threesynthetic steps in the same manner as described for Example 16, butusing 5-bromo-3,4-dihydrospiro[chromene-2,4′-piperidinium]chloride(Intermediate 10) in step 1. LC-MS: m/z=475.0, 477.0 (MH+). ¹H NMR (400MHz, DMSO-d₆): δ 13.91 (br s, 1H), 7.27 (s, 1H), 7.18 (d, 1H), 7.08 (t,1H), 6.89 (d, 1H), 5.85 (s, 2H), 3.67-3.58 (m, 2H), 3.33-3.24 (m, 2H),2.71 (t, 2H), 1.91 (t, 2H), 1.80-1.74 (m, 4H).

Example 23

{5-[3-(5-Bromo-4-oxo-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)isoxazol-5-yl]-2H-tetrazol-2-yl}aceticacid The title compound was prepared, as a yellow solid, through threesynthetic steps in the same manner as described for Example 16, butusing 5-bromospiro[chromene-2,4′-piperidin]-4(3H)-one (Intermediate 11)in step 1. LC-MS: m/z=489.0, 491.0 (MH+). ¹H NMR (500 MHz, acetone-d₆):δ 7.41 (t, 1H), 7.30 (dd, 1H), 7.16 (dd, 1 H), 6.96 (s, 1H), 5.68 (s,2H), 3.75-3.67 (m, 2H), 3.43-3.34 (m, 2H), 2.91 (s, 2H), 2.13-2.04 (m,2H), 1.98-1.88 (m, 2H).

Example 24

{5-[3-(5-Bromo-4-hydroxy-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)isoxazol-5-yl]-2H-tetrazol-2-yl}aceticacid The title compound was prepared, as an off-white solid, in the samemanner as described for Example 20, but using{5-[3-(5-bromo-4-oxo-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)isoxazol-5-yl]-2H-tetrazol-2-yl}aceticacid (Example 23). LC-MS: m/z=491.0, 493.0 (MH+). ¹H NMR (500 MHz,DMSO-d₆): δ 13.90 (br s, 1H), 7.25 (s, 1H), 7.19-7.11 (m, 2H), 6.90 (d,1H), 5.83 (s, 2H), 5.33 (d, 1H), 4.78 (br s, 1H), 3.66-3.60 (m, 1H),3.56-3.50 (m, 1H), 3.49-3.41 (m, 1H), 3.24-3.15 (m, 1H), 2.25-2.15 (m,2H), 1.95 (dd, 1H), 1.92-1.82 (m, 2H), 1.77 (d, 1H).

Example 25

{5-[5-(5-Bromo-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3,4-thiadiazol-2-yl]-2H-tetrazol-2-yl}aceticacid The title compound was prepared, as a white solid, through twosynthetic steps in the same manner as described for Example 17, butusing 5-bromo-3,4-dihydrospiro[chromene-2,4′-piperidinium]chloride(Intermediate 10) in step 1. LC-MS: m/z=492.0, 494.0 (MH+). ¹HNMR (500MHz, DMSO-d₆): δ 13.88 (br s, 1H), 7.18 (d, 1H), 7.09 (t, 1H), 6.90 (d,1H), 5.83 (s, 2H), 3.88-3.81 (m, 2H), 3.63-3.55 (m, 2H), 2.71 (t, 2H),1.92 (t, 2 H), 1.87-1.80 (m, 4H).

Example 26

{5-[5-(5-Bromo-4-oxo-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3,4-thiadiazol-2-yl]-2H-tetrazol-2-yl}aceticacid The title compound was prepared, as a white solid, through twosynthetic steps in the same manner as described for Example 17, butusing 5-bromospiro[chrom-ene-2,4′-piperidin]-4(3H)-one (Intermediate 11)in step 1. LC-MS: m/z=505.9, 507.9 (MH+). ¹H NMR (500 MHz, DMSO-d₆): δ13.88 (br s, 1H), 7.45 (t, 1H), 7.34 (dd, 1H), 7.18 (dd, 1H), 5.83 (s,2H), 3.90-3.83 (m, 2H), 3.65-3.55 (m, 2H), 2.97 (s, 2H), 2.05 (d, 2H),1.98-1.89 (m, 2H).

Example 27

{5-[5-(5-Bromo-4-hydroxy-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3,4-thiadiazol-2-yl]-2H-tetrazol-2-yl}aceticacid The title compound was prepared, as a white solid, in the samemanner as described for Example 20, but using{5-[5-(5-Bromo-4-oxo-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3,4-thiadiazol-2-yl]-2H-tetrazol-2-yl}aceticacid (Example 26). LC-MS: m/z=507.9, 509.9 (MH+). NMR (500 MHz,DMSO-d₆): δ 13.89 (br s, 1H), 7.20 (dd, 1H), 7.15 (t, 1H), 6.92 (dd,1H), 5.82 (s, 2H), 5.38 (d, 1H), 4.83-4.77 (m, 1 H), 3.91-3.87 (m, 1H),3.79-3.70 (m, 2H), 3.54-3.46 (m, 1H), 2.34 (d, 1H), 2.20 (dd, 1H),2.02-1.85 (m, 4H).

Example 28

{5-[2-(5-Bromo-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3-thiazol-5-yl]-2H-tetrazol-2-yl}aceticacid The title compound was prepared, as a white solid, through twosynthetic steps in the same manner as described for Example 21, butusing 5-bromo-3,4-dihydrospiro[chromene-2,4′-piperidinium]chloride(Intermediate 10) in step 1. LC-MS: m/z=491, 493 (MH⁺). ¹H NMR (500 MHz,DMSO-d₆): δ 13.78 (br s, 1H), 7.87 (s, 1H), 7.18 (d, 1 H), 7.08 (t, 1H),6.90 (d, 1H), 5.67 (s, 2H), 3.86-3.79 (m, 2H), 3.53-3.43 (m, 2H), 2.71(t, 2 H), 1.92 (t, 2H), 1.86-1.74 (m, 4H).

Example 29

{5-[2-(5-Bromo-4-oxo-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3-thiazol-5-yl]-2H-tetrazol-2-yl}aceticacid The title compound was prepared, as a pink solid, through 2synthetic steps in the same manner as described for Example 21, butusing 5-bromospiro[chromene-2,4′-piperidin]-4(3H)-one (Intermediate 11)in step 1. LC-MS: m/z=505, 507 (MH⁺). ¹H NMR (400 MHz, DMSO-d₆): δ 13.78(br s, 1H), 7.89 (s, 1H), 7.45 (t, 1H), 7.34 (d, 1H), 7.18 (d, 1H), 5.70(s, 2H), 3.90-3.79 (m, 2H), 3.56-3.44 (m, 2H), 2.97 (s, 2H), 2.04 (d,2H), 1.95-1.82 (m, 2H).

Example 30

{5-[2-(5-Bromo-4-hydroxy-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3-thiazol-5-yl]-2H-tetrazol-2-yl}aceticacid The title compound was prepared, as an off-white solid, in the samemanner as described for Example 20, but using{5-[2-(5-bromo-4-oxo-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3-thiazol-5-yl]-2H-tetrazol-2-yl}aceticacid (Example 29). LC-MS: m/z=507.9, 509.9 (MH+). ¹H NMR (500 MHz,DMSO-d₆): δ 13.77 (br s, 1H), 7.88 (s, 1H), 7.19 (dd, 1H), 7.15 (t, 1H),6.92 (dd, 1H), 5.68 (s, 2H), 5.36 (d, 1H), 4.81-4.77 (m, 1H), 3.87-3.82(m, 1H), 3.76-3.71 (m, 1H), 3.68-3.59 (m, 1H), 3.41-3.35 (m, 1H)2.33-2.30 (m, 1H), 2.19 (dd, 1H), 2.00-1.80 (m, 4H).

Example 31

{5-[5-(5-Iodo-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3,4-thiadiazol-2-yl]-2H-tetrazol-2-yl}aceticacid The title compound was prepared, as a white solid, through twosynthetic steps in the same manner as described for Example 17, butusing 5-iodo-3,4-dihydrospiro[chromene-2,4′-piperidinium]chloride(Intermediate 14) in step 1. LC-MS: m/z=539.9 (MH+). ¹H NMR (400 MHz,DMSO-d₆): δ 13.86 (br s, 1H), 7.44-7.38 (m, 1H), 6.91-6.86 (m, 2H), 5.81(s, 2H), 3.88-3.78 (m, 2H), 3.62-3.51 (m, 2H), 2.60 (t, 2H), 1.89 (t,2H), 1.85-1.74 (m, 4H).

Example 32

{5-[2-(5-Iodo-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3-thiazol-5-yl]-2H-tetrazol-2-yl}aceticacid The title compound was prepared, as a white solid, through 2synthetic steps in the same manner as described for Example 21, butusing 5-iodo-3,4-dihydrospiro[chromene-2,4′-piperidinium]chloride(Intermediate 14) in step 1. LC-MS: m/z=538.9 (MH⁺). ¹H NMR (500 MHz,DMSO-d₆): δ 13.75 (br s, 1H), 7.87 (s, 1H), 7.45-7.40 (m, 1H), 6.92-6.90(m, 2H), 5.69 (s, 2H), 3.85-3.78 (m, 2H), 3.53-3.43 (m, 2H), 2.62 (t,2H), 1.91 (t, 2H), 1.86-1.72 (m, 4H).

Example 33

{5-[2-(5-Iodo-4-oxo-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3-thiazol-5-yl]-2H-tetrazol-2-yl}aceticacid The title compound was prepared, as a white solid, through 2synthetic steps in the same manner as described for Example 21, butusing 5-iodo-4-oxo-3,4-dihydrospiro[chromene-2,4′-piperidinium]chloride(Intermediate 15) in step 1. LC-MS: m/z=552.9 (MH⁺). ¹H NMR (500 MHz,DMSO-d₆): δ 13.77 (br s, 1H), 7.88 (s, 1H), 7.67 (dd, 1H), 7.23 (t, 1H),7.18 (dd, 1H), 5.69 (s, 2H), 3.88-3.79 (m, 2H), 3.52-3.43 (m, 2H), 2.97(s, 2H), 2.04-1.97 (m, 2H), 1.93-1.83 (m, 2H).

Example 34

{5-[5-(8-Chloro-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3,4-thiadiazol-2-yl]-2H-tetrazol-2-yl}aceticacid The title compound was prepared, as a white solid, through 2synthetic steps in the same manner as described for Example 17, butusing 8-chloro-3,4-dihydrospiro[chromene-2,4′-piperidinium]chloride(Intermediate 12) andethyl[5-(5-bromo-1,3,4-thiadiazol-2-yl)-2H-tetrazol-2-yl]acetate(Intermediate 5) in step 1; followed by basic hydrolysis with 1 N NaOHin step 2. LC-MS: m/z=448.0, 450.0 (MH+). NMR (500 MHz, acetone-d₆): δ7.25 (d, 1H), 7.10 (d, 1H), 6.88 (t, 1H), 5.62 (s, 2H), 4.04-3.99 (m,2H), 3.77-3.69 (m, 2H), 2.92 (t, 2H), 2.01-1.92 (m, 6H).

Example 35

{5-[2-(8-Chloro-4-oxo-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3-thiazol-5-yl]-2H-tetrazol-2-yl}aceticacid The title compound was prepared, as a pink solid, through 2synthetic steps in the same manner as described for Example 21, butusing8-chloro-4-oxo-3,4-dihydrospiro[chromene-2,4′-piperidinium]chloride(Intermediate 13) in step 1. LC-MS: m/z=461, 463 (MH⁺). ¹H NMR (400 MHz,DMSO-d₆): δ 13.78 (br s, 1H), 7.89 (s, 1H), 7.81 (dd, 1 H), 7.75 (dd,1H), 7.14-7.09 (m, 1H), 5.70 (s, 2H), 3.93 (d, 2H), 3.52-3.38 (m, 2H),3.01 (s, 2 H), 2.10 (d, 2H), 1.98-1.87 (m, 2H).

Example 36

{5-[2-(5-Methyl-4-oxo-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3-thiazol-5-yl]-2H-tetrazol-2-yl}aceticacid

Step 1: tert-Butyl5-methyl-4-oxo-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidine]-1′-carboxylate.To a degassed mixture of THF (1.0 mL) and water (104 μl) was addedtert-butyl5-bromo-4-oxo-3,4-dihydro-1′-spiro[chromene-2,4′-piperidine]-1′-carboxylate(50.0 mg, 0.13 mmol; Intermediate 10, Step 4), potassiummethyltrifluoroborate (14 mg, 0.12 mmol), PdCl₂(dppf)-CH₂Cl₂ (9.38 mg,0.011 mmol) and cesium carbonate (112 mg, 0.34 mmol). The reactionmixture was stirred at reflux for 16 h in a sealed tube. The volatileswere evaporated under reduced pressure. The resulting residue wasdiluted with water (10 mL)/1N HCl (10 mL) and extracted with DCM (3×5mL) using a separation cartridge. The residue was purified byCombiflash™ chromatography (SiO₂, 12 g, elution with 0-60% EtOAc/hexanesover 40 min) to afford the title compound as an oil.

Step 2: 5-Methylspiro[chromene-2,4′-piperidin]-4(3H)-one. tert-Butyl5-methyl-4-oxo-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidine]-1′-carboxylate(25 mg, 0.08 mmol) was diluted in 4N HCl in dioxane (3 mL) and placed ina round bottom flask equipped with a condenser. The mixture was heatedperiodically (every 10 min) to reflux using a heat gun for a total of 30min. Then the volatiles were evaporated under reduced pressure to affordthe title compound as a solid.

Step 3:tert-Butyl{5-[2-(5-methyl-4-oxo-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3-thiazol-5-yl]-2H-tetrazol-2-yl}acetate.The title compound was prepared in a similar manner as that describedfor Example 5 (step 1) from5-methylspiro[chromene-2,4′-piperidin]-4(3H)-one and Intermediate 3.

Step 4:{5-[2-(5-Methyl-4-oxo-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3-thiazol-5-yl]-2H-tetrazol-2-yl}aceticacid. The title compound was prepared in a similar manner as thatdescribed for Example 9 (step 2) fromtert-butyl{5-[2-(5-methyl-4-oxo-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3-thiazol-5-yl]-2H-tetrazol-2-yl}acetateand LiOH. ¹H NMR (500 MHz, DMSO-d₆): δ 7.87 (s, 1H), 7.43 (t, 1H), 6.97(d, 1H), 6.86 (d, 1H), 5.70-5.66 (m, 2H), 3.84 (d, 3H), 3.48 (t, 2H),2.87 (s, 2H), 2.56 (s, 4H), 2.03 (d, 2H), 1.88-1.85 (m, 2H). MS (+ESI):m/z 441.2 (MH⁺).

Example 37

{5-[2-(4-Hydroxy-5-methyl-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-thiazol-5-yl]-2H-tetrazol-2-yl}aceticacid The title compound was prepared in a similar manner as thatdescribed for Intermediate 1 (step 3) from{5-[2-(5-methyl-4-oxo-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3-thiazol-5-yl]-2H-tetrazol-2-yl}aceticacid and NaBH₄. ¹H NMR (500 MHz, DMSO-d₆): δ 7.84 (s, 2H), 7.07 (t, 2H),6.74 (d, 2H), 6.69 (d, 2H), 5.33 (s, 2H), 5.13 (d, 2H), 4.79-4.76 (m,2H), 3.81 (d, 2H), 3.73 (d, 2H), 3.61-3.57 (m, 2 H), 3.45-3.31 (m,166H), 2.36 (s, 6H), 2.25 (d, 2H), 2.12 (d, 2H), 1.97 (d, 3H), 1.88-1.80(m, 6H). MS (+ESI): m/z 443.1 (MH⁺).

Example 38

{5-[3-(5-Methyl-4-oxo-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)isoxazol-5-yl]-2H-tetrazol-2-yl}aceticacid

Step 1:tert-Butyl{5-[3-(5-methyl-4-oxo-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-4,5-dihydroisoxazol-5-yl]-2H-tetrazol-2-yl}acetate.The title compound was prepared in a similar manner as that describedfor Example 15 (step 1) from5-methylspiro[chromene-2,4′-piperidin]-4(3H)-one and Intermediate 3.

Step 2:tert-Butyl{5-[3-(5-methyl-4-oxo-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)isoxazol-5-yl]-2H-tetrazol-2-yl}acetate.The title compound was prepared in a similar manner as that describedfor Example 15 (step 2) fromtert-butyl{5-[3-(5-methyl-4-oxo-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-4,5-dihydroisoxazol-5-yl]-2H-tetrazol-2-yl}acetateand CAN.

Step 3:{5-[3-(5-Methyl-4-oxo-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)isoxazol-5-yl]-2H-tetrazol-2-yl}aceticacid. The title compound was prepared in a similar manner as thatdescribed for Example 9 (step 2) fromtert-butyl{5-[3-(5-methyl-4-oxo-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)isoxazol-5-yl]-2H-tetrazol-2-yl}acetateand LiOH. ¹H NMR (500 MHz, DMSO-d₆): δ 7.44-7.40 (m, 1H), 7.24 (s, 1H),6.95 (d, 1H), 6.85 (d, 1H), 5.79 (s, 2H), 3.63 (d, 2H), 3.29-3.26 (m,2H), 2.86-2.84 (m, 2H), 2.56 (s, 3H), 1.96 (d, 2H), 1.85-1.78 (m, 2H).MS (+ESI): m/z 425.1 (MH⁺).

Example 39

{5-[5-(5-Vinyl-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3,4-thiadiazol-2-yl]-2H-tetrazol-2-yl}aceticacid

Step 1:tert-Butyl{5-[5-(5-vinyl-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3,4-thiadiazol-2-yl]-2H-tetrazol-2-yl}acetate.To a solution oftert-butyl{5-[5-(5-iodo-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3,4-thiadiazol-2-yl]-2H-tetrazol-2-yl}acetate(50 mg, 0.08 mmol) (Example 31, step 1) in degassed DMF (420 μl) wasadded Pd(Ph₃P)₄ (9.70 mg, 8.40 μmol) and tributyl(vinyl)tin (29.6 μl,0.10 mmol). The reaction mixture was stirred at 80° C. for 16 h. Thereaction mixture was diluted with EtOAc (5 mL)/water (10 mL) and thenacidified with 1N HCl (10 mL). The organic layer was extracted withEtOAc (2×5 mL). The combined organic layers were washed with water (10mL), brine (10 mL), dried on MgSO₄, filtered and evaporated underreduced pressure. The residue was purified by Combiflash™ chromatography(SiO₂, 12 g, elution with 0-40% EtOAc/hexanes over 40 min) to afford thetitle compound as solid.

Step 2:{5-[5-(5-Vinyl-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3,4-thiadiazol-2-yl]-2H-tetrazol-2-yl}aceticacid The title compound was prepared in a similar manner as thatdescribed for Example 9 (step 2) fromtert-butyl{5-[5-(5-vinyl-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3,4-thiadiazol-2-yl]-2H-tetrazol-2-yl}acetateand LiOH. ¹H NMR (500 MHz, DMSO-d₆): δ 7.11-7.08 (m, 1H), 6.93 (dd, 1H),6.80 (dd, 1H), 5.79 (s, 2H), 5.71 (d, 1H), 5.34 (d, 1H), 3.88-3.82 (m,2H), 3.63-3.57 (m, 2H), 2.76 (t, 2H), 1.91-1.81 (m, 6H). MS (+ER): m/z440.1 (MH⁺).

Example 40

{5-[5-(5-Ethyl-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3,4-thiadiazol-2-0]-2H-tetrazol-2-yl}aceticacid

Step 1:tert-Butyl{5-[5-(5-ethyl-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3,4-thiadiazol-2-yl]-2H-tetrazol-2-yl}acetate.To a solution oftert-butyl{5-[5-(5-vinyl-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3,4-thiadiazol-2-yl]-2H-tetrazol-2-yl}acetate(47 mg, 0.1 mmol; Example 39, Step 1) in degassed MeOH (474 μl) wasadded Pd/C (10.09 mg, 0.1 mmol). H₂ was bubble into solution for 2 min.The reaction mixture was stirred at room temperature for 2 h. Thereaction mixture was filtered on celite an evaporated under reducedpressure. The final product was use crud for the next step.

Step 2:{5-[5-(5-Ethyl-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]yl]-2H-tetrazol-2-yl}aceticacid. The title compound was prepared in a similar manner as thatdescribed for Example 8 (step 2) fromtert-butyl{5-[5-(5-ethyl-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3,4-thiadiazol-2-yl]-2H-tetrazol-2-yl}acetateand TFA. ¹H NMR (400 MHz, DMSO-d₆): δ 7.06 (t, 1H), 6.76 (d, 1H), 6.70(d, 1H), 5.84 (s, 2H), 3.86 (dt, 2H), 3.65-3.57 (m, 2H), 2.70 (t, 2H),2.59 (q, 2H), 1.89-1.80 (m, 6H), 1.17 (t, 3H). MS (+ESI): m/z 442.2(MH⁺).

Example 41

{5-[3-(5-methyl-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)isoxazol-5-yl]-2H-tetrazol-2-yl}aceticacid The title compound was prepared in a similar manner as thatdescribed for Example 36 (step 1) from{5-[3-(5-bromo-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)isoxazol-5-yl]-2H-tetrazol-2-yl}aceticacid (Example 22) and potassium methyltrifluoroborate. ¹H NMR (500 MHz,DMSO-d₆): δ 7.14 (s, 1H), 6.98 (t, 1H), 6.71 (d, 1 H), 6.67 (d, 1H),4.97 (s, 3H), 3.63-3.58 (m, 3H), 3.45-3.39 (m, 7H), 2.62 (t, 2H), 2.19(s, 3H), 1.86 (t, 2H), 1.78-1.68 (m, 10H). MS (+ESI): m/z 411.2 (MH⁺).

Example 42

{5-[2-(5-Methyl-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3-thiazol-5-yl]-2H-tetrazol-2-yl}aceticacid The title compound was prepared in a similar manner as thatdescribed for Example 36 (step 1) from{5-[2-(5-bromo-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3-thiazol-5-yl]-2H-tetrazol-2-yl}aceticacid (Example 28) and potassium methyltrifluoroborate. ¹H NMR (500 MHz,DMSO-d₆): δ 7.87-7.86 (m, 1H), 6.99 (t, 1H), 6.73 (d, 1H), 6.69-6.67 (m,1H), 5.68 (m, 2H), 3.84-3.79 (m, 2H), 3.51-3.46 (m, 2H), 2.62 (t, 2H),2.19 (s, 3H), 1.89-1.75 (m, 6H). MS (+ESI): m/z 427.2 (MH⁺).

Example 43

{5-[5-(5-Methyl-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3,4-thiadiazol-2-yl]-2H-tetrazol-2-yl}aceticacid The title compound was prepared in a similar manner as thatdescribed for Example 36 (step 1) from{5-[5-(5-bromo-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3,4-thiadiazol-2-yl]-2H-tetrazol-2-yl}aceticacid (Example 25) and potassium methyltrifluoroborate. ¹H NMR (500 MHz,DMSO-d₆): δ 7.00 (t, 1H), 6.73 (d, 1H), 6.69 (d, 1H), 5.82 (s, 2H),3.86-3.83 (m, 2H), 3.59 (t, 2H), 2.65-2.61 (m, 2H), 2.19 (s, 3H),1.90-1.80 (m, 6H). MS (+ESI): m/z 428.2 (MH⁺).

Example 44

{5-[2-(8-Bromo-5-fluoro-4-oxo-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3-thiazol-5-yl]-2H-tetrazol-2-yl}aceticacid

Step 1: 8-Bromo-5-fluorospiro[chromene-2,4′-piperidin]-4(3H)-onehydrochloride The title compound was prepared in a similar manner asthat described for Intermediate 1 (steps 1 and 2) and follow by theprocedure detail in Example 36 (step 2), starting from2-bromo-5-fluorophenol.

Step 2:{5-[2-(8-Bromo-5-fluoro-4-oxo-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3-thiazol-5-yl]-2H-tetrazol-2-yl}aceticacid. The title compound was prepared in a similar manner as thatdescribed for Example 14 (steps 1 and 2) from Intermediate 3 and8-bromo-5-fluorospiro[chromene-2,4′-piperidin]-4(3H)-one hydrochloride.¹H NMR (500 MHz, DMSO-d₆): δ 7.94 (dd, 1H), 7.88 (s, 1H), 6.92 (dd, 1H),5.65 (s, 2H), 3.96-3.91 (m, 2H), 3.48-3.41 (m, 2H), 2.98 (s, 2H),2.13-2.08 (m, 2H), 1.95-1.88 (m, 2H). MS (+ESI): m/z 522.9, 523.9 (MH⁺).

Example 45

{5-[2-(1-Oxo-1,4-dihydro-1′H-spiro[isochromene-3,4′-piperidin]-1′-yl)-1,3-thiazol-5-yl]-2H-tetrazol-2-yl}aceticacid

Step 1:tert-Butyl{5-[2-(1-oxo-1,4-dihydro-1′H-spiro[isochromene-3,4′-piperidin]-1′-yl)-1,3-thiazol-5-yl]-2H-tetrazol-2-yl}acetate.The title compound was prepared in a similar manner as that describedfor Example 5 (step 1) from Intermediate 3 andspiro[isochromene-3,4′-piperidin]-1(4H)-one hydrochloride.

Step 2:{5-[2-(1-Oxo-1,4-dihydro-1′H-spiro[isochromene-3,4′-piperidin]-1′-yl)-1,3-thiazol-5-yl]-2H-tetrazol-2-yl}aceticacid. The title compound was prepared in a similar manner as thatdescribed for Example 8 (step 2) fromtert-Butyl{5-[2-(1-oxo-1,4-dihydro-1′H-spiro[isochromene-3,4′-piperidin]-1′-yl)-1,3-thiazol-5-yl]-2H-tetrazol-2-yl}acetate.and TFA. ¹H NMR (400 MHz, DMSO-d₆): δ 7.97 (d, 1H), 7.89 (s, 1H),7.70-7.65 (m, 1H), 7.50-7.45 (m, 1H), 7.41 (d, 1H), 5.71 (s, 2H),3.86-3.80 (m, 2H), 3.56-3.47 (m, 2H), 3.23 (s, 2H), 1.96-1.90 (m, 4H).MS (+ESI): m/z 427.20 (MH⁺).

Example 46

{5-[2-(8-Chloro-1-oxo-1,4-dihydro-1′H-spiro[isochromene-3,4′-piperidin]-1′-yl)-1,3-thiazol-5-yl]-2H-tetrazol-2-yl}aceticacid

Step 1:tert-Butyl{5-[2-(8-chloro-1-oxo-1,4-dihydro-1′H-spiro[isochromene-3,4′-piperidin]-1′-yl)-1,3-thiazol-5-yl]-2H-tetrazol-2-yl}acetate.The title compound was prepared in a similar manner as that describedfor Example 5 (step 1) from Intermediate 3 and Intermediate 16.

Step 2:{5-[2-(8-Chloro-1-oxo-1,4-dihydro-1′H-spiro[isochromene-3,4′-piperidin]-1′-yl)-1,3-thiazol-5-yl]-2H-tetrazol-2-yl}aceticacid. The title compound was prepared in a similar manner as thatdescribed for Example 8 (step 2) fromtert-butyl{5-[2-(8-chloro-1-oxo-1,4-dihydro-1′H-spiro[isochromene-3,4′-piperidin]-1′-yl)-1,3-thiazol-5-yl]-2H-tetrazol-2-yl}acetateand TFA. ¹H NMR (500 MHz, DMSO-d₆): δ 7.88 (s, 1H), 7.64-7.60 (m, 1H),7.54 (d, 1H), 7.37 (d, 1H), 5.69 (s, 2H), 3.80 (d, 2H), 3.55-3.47 (m,2H), 3.26 (s, 2H), 1.94-1.84 (m, 4H). MS (+ESI): m/z 461.10 (MH⁺).

Example 47

{5-[5-(8-Chloro-1-oxo-1,4-dihydro-1′H-spiro[isochromene-3,4′-piperidin]-1′-yl)-1,3,4-thiadiazol-2-yl]-2H-tetrazol-2-yl}aceticacid

Step 1:tert-Butyl{5-[5-(8-chloro-1-oxo-1,4-dihydro-1′H-spiro[isochromene-3,4′-piperidin]-1′-yl)-1,3,4-thiadiazol-2-yl]-2H-tetrazol-2-yl}acetate.The title compound was prepared in a similar manner as that describedfor Example 13 (step 1) from Intermediate 6 and Intermediate 16.

Step 2:{5-[2-(8-Chloro-1-oxo-1,4-dihydro-1′H-spiro[isochromene-3,4′-piperidin]-1′-yl)-1,3-thiazol-5-yl]-2H-tetrazol-2-yl}aceticacid. The title compound was prepared in a similar manner as thatdescribed for Example 8 (step 2) fromtert-butyl{5-[5-(8-chloro-1-oxo-1,4-dihydro-1′H-spiro[isochromene-3,4′-piperidin]-1′-yl)-1,3,4-thiadiazol-2-yl]-2H-tetrazol-2-yl}acetate.and TFA. ¹H NMR (500 MHz, DMSO-d₆): δ 7.62 (d, 1H), 7.55 (d, 1H), 7.37(d, 1H), 5.82 (s, 2H), 3.83 (s, 2H), 3.60 (s, 2H), 3.27 (s, 2H),1.94-1.89 (m, 4H). MS (+ESI): m/z 462.0 (MH⁺).

Example 48

{5-[3-(8-Chloro-1-oxo-1,4-dihydro-1′H-spiro[isochromene-3,4′-piperidin]-1′-yl)isoxazol-5-yl]-2H-tetrazol-2-yl}aceticacid

Step 1:tert-Butyl{5-[3-(8-chloro-1-oxo-1,4-dihydro-1′H-spiro[isochromene-3,4′-piperidin]-1′-yl)-4,5-dihydroisoxazol-5-yl]-2H-tetrazol-2-yl}acetate.The title compound was prepared in a similar manner as that describedfor Example 15 (step 1) from Intermediate 7 and Intermediate 16.

Step 2:tert-Butyl{5-[3-(8-chloro-1-oxo-1,4-dihydro-1′H-spiro[isochromene-3,4′-piperidin]-1′-yl)isoxazol-5-yl]-2H-tetrazol-2-yl}acetate.The title compound was prepared in a similar manner as that describedfor Example 15 (step 2) fromtert-butyl{5-[3-(8-chloro-1-oxo-1,4-dihydro-1′H-spiro[isochromene-3,4′-piperidin]-1′-yl)-4,5-dihydroisoxazol-5-yl]-2H-tetrazol-2-yl}acetateand CAN.

Step 3:{5-[3-(8-Chloro-1-oxo-1,4-dihydro-1′H-spiro[isochromene-3,4′-piperidin]-1′-yl)isoxazol-5-yl]-2H-tetrazol-2-yl}aceticacid. The title compound was prepared in a similar manner as thatdescribed for Example 8 (step 2) fromtert-Butyl{5-[3-(8-chloro-1-oxo-1,4-dihydro-1′H-spiro[isochromene-3,4′-piperidin]-1′-yl)isoxazol-5-yl]-2H-tetrazol-2-yl}acetateand TFA. ¹H NMR (400 MHz, DMSO-d₆): δ 7.64-7.59 (m, 1H), 7.55 (d, 1H),7.38 (d, 1H), 7.26 (s, 1H), 5.86 (s, 2H), 3.59 (s, 2H), 3.34 (d, 2H),3.26 (s, 2H), 1.87-1.80 (m, 4H). MS (+ESI): m/z 445.0 (MH⁺).

Example 49

(5-{2-[4-Oxo-5-(trifluoromethyl)-3,4-dihydro-1′H-spiro[1,3-benzoxazine-2,4′-piperidin]-1′-yl]-1,3-thiazol-5-yl}-2H-tetrazol-2-yl)aceticacid

Step 1: 2-Fluoro-6-(trifluoromethyl)benzamide. To a solution of2-fluoro-6-(trifluoromethyl)benzoic acid (1 g, 4.81 mmol) in THF (24.0mL) was added a few drops of DMF and oxalyl chloride (1.05 ml, 12.01mmol) at 0° C. The reaction mixture was stirred at room temperature for1.5 h. The volatiles were evaporated under reduced pressure. The residuewas diluted with THF and evaporated under reduced pressure. The sameprocess was repeated several times. The residue was dissolved in THF andammonia gas was bubble into solution for 5 min. The reaction mixture wasstirred at room temperature for 1.5 h. The solvent was evaporated underreduced pressure. The residue was triturated with DCM/hexanes (1/10),filtered, washed with hexanes and dried to afford the title compound asa solid.

Step 2: 2-Hydroxy-6-(trifluoromethyl)benzamide. To a solution of2-fluoro-6-(trifluoromethyl)benzamide (500 mg, 2.41 mmol) in diglyme(8.05 mL) was added potassium trimethylsilanolate (1.08 g, 8.45 mmol).The reaction mixture was stirred at 120° C. overnight. The reactionmixture was acidified with 1N HCl (30 mL) and extracted with EtOAc (3×10mL). The combined organic layers were washed with 10% solution of LiClin water, dried with MgSO₄, filtered and evaporated under reducedpressure. The resulting residue was purified by Combiflash™chromatography (SiO₂, 12 g, elution with 20-40% EtOAc/hexanes over 40min) to afford the title compound as solid.

Step 3:(5-{2-[4-Oxo-5-(trifluoromethyl)-3,4-dihydro-1′H-spiro[1,3-benzoxazine-2,4′-piperidin]-1′-yl]-1,3-thiazol-5-yl}-2H-tetrazol-2-yl)aceticacid. To a solution of Intermediate 17 (42 mg, 0.13 mmol) and2-hydroxy-6-(trifluoromethyl)benzamide (28.2 mg, 0.14 mmol) in toluene(624 μL) was added p-toluenesulfonic acid monohydrate (9.50 mg, 0.05mmol). The reaction mixture was stirred at 140° C. for 30 min. Thesolvent was evaporated under reduced pressure. The resulting residue waspurified by Combiflash™ chromatography (SiO₂, 12 g, elution with 0-5%MeOH/DCM over 40 min) to afford the title compound as solid. ¹H NMR (500MHz, DMSO-d₆): δ 9.14 (s, 2H), 7.85 (s, 1H), 7.73 (s, 1H), 7.56 (s, 1H),7.49 (s, 1H), 5.33 (s, 2H), 3.88 (d, 4H), 3.48 (s, 2H), 2.15 (s, 3H),2.00-1.97 (m, 3H). MS (+ESI): m/z 496.2 (MH⁺).

Example 50

{5-[2-(8-Chloro-4-oxo-3,4-dihydro-1′H-spiro[1,3-benzoxazine-2,4′-piperidin]-1′-yl)-1,3-thiazol-5-yl]-2H-tetrazol-2-yl}aceticacid

Step 1: 3-Chloro-2-hydroxybenzamide. A mixture of3-chloro-2-hydroxybenzoic acid (335 mg, 1.94 mmol), DIPEA (2.98 mL,17.08 mmol), HATU (849 mg, 2.232 mmol) was dissolved in DMF (1.94mL)/THF (7.77 mL). The reaction was stirred for 15 min, then ammoniumchloride (457 mg, 8.54 mmol) was added. The reaction mixture was stirredat room temperature overnight. The volatiles were evaporated underreduced pressure. The residue was diluted with saturated 1N HCl (20 mL)and extracted with EtOAc (3×5 mL). The combined organic fractions werewashed with water (30 mL), sat. NaHCO₃ (20 mL), brine (20 mL), driedover MgSO₄ and evaporated under reduced pressure. The resulting residuewas purified by Combiflash™ chromatography (SiO₂, 12 g, elution with10-70% EtOAc/hexanes over 40 min) to afford the title compound as solid.

Step 2:{Ethyl{5-[2-(8-chloro-4-oxo-3,4-dihydro-1′H-spiro[1,3-benzoxazine-2,4′-piperidin]-1′-yl)-1,3-thiazol-5-yl]-2H-tetrazol-2-yl}acetate.The title compound was prepared in a similar manner as that describedfor Example 49 (step 3) from Intermediate 17 and3-chloro-2-hydroxybenzamide.

Step 3:{5-[2-(8-Chloro-4-oxo-3,4-dihydro-1′H-spiro[1,3-benzoxazine-2,4′-piperidin]-1′-yl)-1,3-thiazol-5-yl]-2H-tetrazol-2-yl}aceticacid. The title compound was prepared in a similar manner as thatdescribed for Example 9 (step 2) from{ethyl{5-[2-(8-chloro-4-oxo-3,4-dihydro-1′H-spiro[1,3-benzoxazine-2,4′-piperidin]-1′-yl)-1,3-thiazol-5-yl]-2H-tetrazol-2-yl}acetateand LiOH. ¹H NMR (500 MHz, DMSO-d₆): δ 9.04 (s, 1H), 7.90 (s, 1H), 7.76(dd, 1H), 7.73 (dd, 1H), 7.17 (t, 1H), 5.70 (s, 2H), 4.01-3.97 (m, 2H),3.46-3.41 (m, 2H), 2.24-2.20 (m, 2H), 1.98-1.96 (m, 2H). MS (+ESI): m/z462.1 (MH⁺).

Example 51

{5-[3-(5-Methyl-4-oxo-3,4-dihydro-1′H-spiro[1,3-benzoxazine-2,4′-piperidin]-1′-yl)isoxazol-5-yl]-2H-tetrazol-2-yl}aceticacid

Step 1: 2-Hydroxy-6-methylbenzamide. A solution of ethyl2-hydroxy-6-methylbenzoate (600 mg, 3.33 mmol) was dissolved in methanol(10 mL) and cooled to 0° C. Ammonia gas was bubble into solution for 5min. A catalytic amount of KCN was added and the reaction was allowed towarm to room temperature. After 30 min, the reaction mixture was stirredat 60° C. overnight. The volatiles were evaporated under reducedpressure. The resulting residue was triturated with DCM/hexanes (1:10),filtered, washed with hexanes and dried.

Step 2: Benzyl5-methyl-4-oxo-3,4-dihydro-1′H-spiro[1,3-benzoxazine-2,4′-piperidine]-1′-carboxylate.The title compound was prepared in a similar manner as that describedfor Example 49 (step 3) from 2-hydroxy-6-methylbenzamide and benzyl4-oxopiperidine-1-carboxylate.

Step 3: 5-Methylspiro[1,3-benzoxazine-2,4′-piperidin]-4(3)-one. To asolution of benzyl5-methyl-4-oxo-3,4-dihydro-1′H-spiro[1,3-benzoxazine-2,4′-piperidine]-1′-carboxylate(293 mg, 0.80 mmol) in degassed MeOH (4.00 mL) was added Pd/C (85 mg,0.80 mmol), then H₂ (1.61 mg, 0.80 mmol) was bubbled into the solutionfor 5 min. The reaction was stirred at room temperature for 1.5 h. Thereaction mixture was filtered on Celite™ and the solvent was evaporatedunder reduced pressure to afford the title compound as a solid. Step 4:tert-Butyl{5-[3-(5-methyl-4-oxo-3,4-dihydro-1′H-spiro[1,3-benzoxazine-2,4′-piperidin]-1′-yl)-4,5-dihydroisoxazol-5-yl]-2H-tetrazol-2-yl}acetate.The title compound was prepared in a similar manner as that describedfor Example 15 (step 1) from Intermediate 7 and5-methylspiro[1,3-benzoxazine-2,4′-piperidin]-4(3)-one.

Step 5:tert-Butyl{5-[3-(5-methyl-4-oxo-3,4-dihydro-1′H-spiro[1,3-benzoxazine-2,4′-piperidin]-1′-yl)isoxazol-5-yl]-2H-tetrazol-2-yl}acetate.The title compound was prepared in a similar manner as that describedfor Example 15 (step 2) fromtert-butyl{5-[3-(5-methyl-4-oxo-3,4-dihydro-1′H-spiro[1,3-benzoxazine-2,4′-piperidin]-1′-yl)-4,5-dihydroisoxazol-5-yl]-2H-tetrazol-2-yl}acetateand CAN.

Step 6:{5-[3-(5-Methyl-4-oxo-3,4-dihydro-1′H-spiro[1,3-benzoxazine-2,4′-piperidin]-1′-yl)isoxazol-5-yl]-2H-tetrazol-2-yl}aceticacid. The title compound was prepared in a similar manner as thatdescribed for Example 9 (step 2) fromtert-butyl{5-[3-(5-methyl-4-oxo-3,4-dihydro-1′H-spiro[1,3-benzoxazine-2,4′-piperidin]-1′-yl)isoxazol-5-yl]-2H-tetrazol-2-yl}acetateand LiOH. ¹H NMR (500 MHz, DMSO-d₆): δ 8.67-8.66 (m, 1H), 7.36 (d, 1H),7.26 (s, 1H), 6.93-6.90 (m, 2H), 5.78 (s, 2H), 3.69-3.66 (m, 2H),3.31-3.27 (m, 2H), 2.61 (s, 3H), 2.06-2.03 (m, 2H), 1.92-1.88 (m, 2H) MS(+ESI): m/z 426.1 (MH⁺).

The Examples listed in Table 1 were prepared essentially following theprocedures outlined for Examples 49-51.

TABLE 1 Characterisation by Mass Example Structure Spectrometry 52

MS: m/z 530.0 (MH⁺) 53

MS: m/z 444.2 (MH⁺) 54

MS: m/z 462.0 (MH⁺) 55

MS: m/z 442.2 (MH⁺) 56

MS: m/z 462.1 (MH⁺)

Example 57

{5-[2-(5-Ethoxy-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3-thiazol-5-yl]-2H-tetrazol-2-yl}aceticacid

Step 1. Benzyl5-hydroxy-4-oxo-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidine]-1′-carboxylateTo a solution of benzyl 4-oxopiperidine-1-carboxylate (2.67 g, 11.45mmol) in methanol (25 ml) was added freshly distilled pyrrolidine (1.2ml, 14.51 mmol), followed by hydroxyphenone (2.07 g, 13.61 mmol). Themixture was stirred at an external temperature of 75° C. for 90 min,then cooled to room temperature and concentrated. The resulting oilyresidue was purified by flash chromatography on silica gel (eluting with20% to 80% EtOAc in hexane) to give the title compound as a pale yellowoil.

Step 2. Benzyl4,5-dihydroxy-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidine]-1′-carboxylateTo a solution of benzyl5-hydroxy-4-oxo-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidine]-1′-carboxylate(3.96 g, 10.78 mmol) in THF (15 ml) and MeOH (35 ml), stirred at 0° C.,was added portion wise solid sodium borohydride (588 mg, 15.54 mmol).The reaction was stirred at 0° C. for 1 h, then quenched at 0° C. by theaddition of acetone. The reaction was diluted with DCM, washed with 5%KHSO₄, dried over MgSO₄, filtered and concentrated to give the titlecompound as a white foam.

Step 3: Benzyl5-ethoxy-4-hydroxy-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidine]-1′-carboxylateand Benzyl 5-ethoxy-1′H-spiro[chromene-2,4′-piperidine]-1′-carboxylate Asolution of benzyl4,5-dihydroxy-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidine]-1′-carboxylate(570 mg, 1.54 mmol) in DME (5 ml) was treated with potassium carbonate(639 mg, 4.62 mmol), followed by neat ethyl bromide (1700 mg, 15.6mmol). The mixture was stirred at room temperature for 68 h, thendiluted with DCM, washed with 1M NaOH, dried over MgSO₄ filtered andconcentrated. The resulting crude mixture was used in the next stepwithout further purification.

Step 4: 5-Ethoxy-3,4-dihydrospiro[chromene-2,4′-piperidine] To a mixtureof benzyl5-ethoxy-4-hydroxy-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidine]-1′-carboxylate,and benzyl 5-ethoxy-1′H-spiro[chromene-2,4′-piperidine]-1′-carboxylate(1.54 mmol) was added solid 10% Pd on carbon (350 mg, 21 mol %),followed by the addition of MeOH (60 ml) via a cannula. The reaction wasstirred under vacuum for 3 min. A balloon filled with H₂ was attached tothe reaction vessel and the reaction mixture was stirred under ahydrogen atmosphere at room temperature for 1 h. Then 10 M HCl (0.4 mL,4 mmol) was added, and the reaction was stirred under a H₂ atmosphereovernight. The reaction mixture was then filtered through a pad ofCelite™ and concentrated. The resulting mixture was dissolved in DCM andwashed with 1M NaOH in water, dried over MgSO₄, filtered andconcentrated to give the title compound.

Step 5:tert-butyl[5-({[(5-ethoxy-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)(imino)methyl]sulfanyl}methyl)-2-H-tetrazol-2-yl]acetate A mixture of5-ethoxy-3,4-dihydrospiro[chromene-2,4′-piperidine] (78 mg, 0.315 mmol),tert-butyl[5-(2-bromo-1,3-thiazol-5-yl)-2H-tetrazol-2-yl]acetate (96 mg,0.277 mmol), and K₂CO₃ (127 mg, 0.919 mmol) was suspended in dry diglyme(1.5 ml). The reaction vial was sealed and the reaction was stirredunder N₂ at external temperature of 110° C. for 2.5 h. The reaction wasthen cooled, diluted with EtOAc, washed with sat. NaHCO₃ and water,dried over MgSO₄, filtered and concentrated. The resulting brown oilyresidue was purified by flash chromatography on silica gel (eluting with5% to 50% EtOAc in hexane) to give the title compound as a pale yellowsolid.

Step 6:{5-[2-(5-ethoxy-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3-thiazol-5-yl]-2H-tetrazol-2-yl}aceticacid To a solution oftert-butyl[5-({[(5-ethoxy-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)(imino)methyl]sulfanyl}methyl)-2H-tetrazol-2-yl]acetate (5.1 mg, 9.95 μmol) inTHF (1 ml) and ethanol (0.5 ml) was added a solution of NaOH (10 mg,0.250 mmol) in water (0.25 ml). The resulting suspension was stirred at0° C. for 2 h, then diluted with DCM, washed with 5% KHSO₄ in water(final pH=1.5), dried over MgSO₄, filtered and concentrated. Theresulting residue was purified by flash chromatography on silica gel(eluting with 1% to 40% MeOH in DCM) to give the title compound as anoff white solid. ¹H NMR (MeOH-d₄): δ 7.82 (1H, s), 7.05 (1H, t), 6.49(2H, m), 5.27 (2H, s), 4.05 (2H, q), 3.88 (2H, d), 3.59 (2H, t), 2.72(2H, t), 1.95 (2H, d), 1.90-1.83 (4H, m), 1.45 (3H, t). MS: m/z 457(MH⁺).

Example 58

(3-{2-[5-(Cyclopropylmethoxy)-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl]-1,3-thiazol-5-yl}-2-oxo-2,3-dihydro-1H-imidazol-1-yl)aceticacid

Step 1: 3,4-Dihydrospiro[chromene-2,4′-piperidin]-5-ol To a solution ofbenzyl4,5-dihydroxy-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidine]-1′-carboxylate(853 mg, 2.31 mmol) in ethanol (20 ml) was added solid 10% Pd on carbon(361 mg, 15 mol %), followed by 10 M HCl in water (2 mL, 20 mmol). Afterstirring under vacuum for 5 min, a balloon filled with H₂ was attachedto the reaction vessel and the reaction was stirred under a hydrogenatmosphere at room temperature for 48 h. The reaction mixture was thenfiltered through a pad of Celite™ and concentrated three times in thepresence of dry EtOH (co-distillation) to give the title compound as apale beige foam.

Step 2:l′-(5-Bromo-1,3-thiazol-2-yl)-3,4-dihydrospiro[chromene-2,4′-piperidin]-5-olA mixture of 3,4-dihydrospiro[chromene-2,4′-piperidin]-5-ol (504 mg,2.30 mmol), 2,5-dibromothiazole (583 mg, 2.400 mmol), and K₂CO₃ (795 mg,5.75 mmol) was suspended in dry DMSO (5 ml), and stirred under N₂ at anexternal temperature of 110° C. for 2 h. The reaction mixture was thencooled down to room temperature, and poured on 5% KHSO₄ in water. Afterstirring for 10 min, the precipitate was collected to give the titlecompound as a brown solid residue, which was stored under vacuum for 5 hprior to use.

Step 3:1′-(5-bromo-1,3-thiazol-2-yl)-5-(cyclopropylmethoxy)-3,4-dihydrospiro[chromene-2,4′-piperidine]hromene-2,4′-piperidine]A solution of1′-(5-bromo-1,3-thiazol-2-yl)-3,4-dihydrospiro[chromene-2,4′-piperidin]-5-ol(227 mg, 0.595 mmol) and triphenylphosphine (356 mg, 1.357 mmol) in dryTHF (2 ml), stirred under N₂ at 0° C., was treated with neat cyclopropylmethanol (135 mg, 1.87 mmol), followed by DEAD (0.165 ml, 1.04 mmol).The reaction mixture was stirred at the same temperature for 30 min andthen at room temperature overnight. The reaction mixture was thenconcentrated and purified by flash chromatography on silica gel (elutingwith 3% to 10% EtOAc in hexane) to give the title compound as a whitesolid.

Step 4: Ethyl(3-{2-[5-(cyclopropylmethoxy)-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl]-1,3-thiazol-5-yl}-2-oxo-2,3-dihydro-1H-imidazol-1-yl)acetateA mixture1′-(5-bromo-1,3-thiazol-2-yl)-5-(cyclopropylmethoxy)-3,4-dihydrospiro[chromene-2,4′-piperidine]hromene-2,4′-piperidine](61.5 mg, 0.141 mmol), 2-imidazolone (41 mg, 0.241 mmol), copper(I)iodide (25 mg, 0.131 mmol) and potassium phosphate tribasic (104 mg,0.490 mmol) was suspended in dry dioxane (1.5 ml), stirred under vacuumfor 3 min, and then backfilled with N₂. The reaction mixture was treatedwith neat dimethyl ethylenediamine (24.68 mg, 0.28 mmol) in a sealedvial, which was covered with aluminum foil and placed in an oil bathpreheated to 95° C. The mixture was stirred at 95° C. for 3.5 h, thendiluted with DCM, washed with sat. NH₄Cl plus some 5% KHSO₄, dried overMgSO₄, filtered and concentrated. The resulting oily residue waspurified by flash chromatography on silica gel (eluting with 10% to 100%EtOAc in hexane) to give the title compound as a white solid.

Step 5:(3-{2-[5-(cyclopropylmethoxy)-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl]-1,3-thiazol-5-yl}-2-oxo-2,3-dihydro-1H-imidazol-1-yl)aceticacid A solution of ethyl(3-{2-[5-(cyclopropylmethoxy)-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl]-1,3-thiazol-5-yl}-2-oxo-2,3-dihydro-1H-imidazol-1-yl)acetate(38 mg, 0.072 mmol) in THF (1.5 ml) and ethanol (1 ml), stirred at 0°C., was treated with a solution of sodium hydroxide (51 mg, 1.275 mmol)in water (1 mL). The reaction was stirred at 0° C. for 1.5 h. Thereaction mixture was then diluted with DCM, washed with a solution of 5%KHSO₄ in water, dried over MgSO₄, filtered and concentrated to provide aresidue, which was further triturated with ether-hexane, filtered anddried to give the title compound as a white solid. ¹H NMR (DMSO-d₆):δ7.25 (1H, s), 7.07 (1H, t), 6.94 (1H, s), 6.77 (1H, s), 6.45 (2H, m),4.33 (2H, s), 3.82 (2H, d), 3.67 (2H, d), 2.61 (2 H, s), 1.81 (4H, d),1.73 (2H, d), 1.24 (1H, m), 0.58 (2H, d), 0.35 (2H, d). (two protons aremissing because their signals overlap with that of the solvent). MS: m/z497 (MH⁺).

The following Examples were prepared in the manner previously describedfor similar analogs. Example 59 was prepared according to the synthesisdescribed in Example 16. Examples 60 and 61 were prepared according tothe synthesis described in Example 57. Examples 63, 64 and 65 wereprepared according to the synthesis described in Example 21. Example 62was prepared by the alkylation of the compound of Example 63 with3,4-difluorobenzyl bromide.

TABLE 2 Characterisation by Example Structure Mass Spectrometry 59

MS: m/z 427 (MH⁺) 60

MS: m/z 475 (MH⁺) 61

MS: m/z 471 (MH⁺) 62

MS: m/z 555 (MH⁺) 63

MS: m/z 443 (MH⁺) 64

MS: m/z 457 (MH⁺) 65

MS: m/z 443 (MH⁺)

Example 66

{3-[3-(5-Chloro-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)isoxazol-5-yl]-2-oxo-2,3-dihydro-1H-imidazol-1-yl}aceticacid

Step 1: Ethyl3-(5-chloro-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-4,5-dihydroisoxazole-5-carboxylateA mixture of 3-bromo-4,5-dihydroisoxazole-5-carboxylate from Example 2,step 1 (3.37 g, 15 mmol),5-chloro-3,4-dihydrospiro[chromene-2,4′-piperidine] (3.8 g, 16 mmol) andDIPEA (5.8 g, 45 mmol) in EtOH (30 mL) was refluxed overnight. Theresulting mixture was cooled to room temperature, adjusted to pH 5 with1 M HCl, and then extracted with EtOAc (20 mL×2). The combined organiclayers were washed with brine (10 mL), dried over Na₂SO₄ andconcentrated. The resulting residue was purified by columnchromatography on silica gel (PE/EA=5/1) to afford the title compound.¹H NMR (CDCl₃ 400 MHz) δ 7.04 (t, 1H), 6.93 (d, 1H), 6.75 (d, 1H),4.95-4.99 (m, 1H), 4.25 (q, 2H), 3.41-3.44 (m, 2H), 3.23-3.36 (m, 4H),2.77 (t, 2H), 1.80-1.85 (m, 4H), 1.61-1.68 (m, 2H), 1.34 (t, 3H).

Step 2:3-(5-Chloro-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)isoxazole-5-carboxylicacid To a mixture of ethyl3-(5-chloro-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-4,5-dihydroisoxazole-5-carboxylate(2.53 g, 6.7 mmol), NaOAc (1.43 g, 17.4 mmol) in chlorobenzene (20 mL)was added I₂ (2.2 g, 8.7 mmol). The mixture was stirred at 110° C.overnight. After cooling, the resulting mixture was quenched with 10%Na₂S₂O₃ (50 mL), and extracted with EtOAc (60 mL×2). The combinedorganic layers were washed with brine (30 mL), dried over Na₂SO₄ andconcentrated under vacuum. The crude residue was purified by columnchromatography on silica gel (PE/EA=20/1) to afford ethyl3-(5-chloro-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)isoxazole-5-carboxylate.

To a stirred solution of ethyl3-(5-chloro-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)isoxazole-5-carboxylate(2.05 g, 5.4 mmol) in THF (20 mL) was added 1 M LiOH (21.8 mL). Themixture was stirred at room temperature for 1 hour, then the solvent wasevaporated under vacuum. The resulting residue was diluted with water (5mL), adjusted to pH 3 with 1 M HCl, and then extracted with Et₂O (10mL×3). The combined organic layers were washed with brine (5 mL), driedover Na₂SO₄ and concentrated under vacuum. The resulting crude productwas washed with n-hexane (30 mL) and filtered to afford the titlecompound. ¹H NMR (CD₃OD 400 MHz) δ 7.07 (t, 1H), 6.93 (d, 1H), 6.80 (d,1H), 6.94 (s, 1H), 3.52-3.57 (m, 2H), 3.27-3.32 (m, 2H), 2.81 (t, 2H),1.77-1.92 (m, 6H).

Step 3:3-(5-Chloro-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)isoxazol-5-amineTo a mixture of3-(5-chloro-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)isoxazole-5-carboxylicacid (1.9 g, 5.5 mmol) and TEA (1.5 mL, 11 mmol) in 2-methylpropan-2-ol(20.2 g, 273 mmol) was added DPPA (7.5 g, 27.3 mmol). The mixture wasstirred at 90° C. overnight under N₂. Solvent was removed under vacuum.The resulting residue was purified by column chromatography on silicagel (PE/EA=10/1) to afford crudetert-butyl[3-(5-chloro-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)isoxazol-5-yl]carbamate.

A mixture of crudetert-butyl[3-(5-chloro-3,4-dihydro-1′H-spiro-[chromene-2,4′-piperidin]-1′-yl)isoxazol-5-yl]carbamateand 4M HCl in dioxane (50 mL) was stirred at room temperature overnight.The volatile materials were removed under vacuum. The resulting residuewas diluted with water (10 mL), treated with NaOH (0.32 g, 8 mmol), thenstirred for 1 hour and extracted with EtOAc (10 mL×3). The combinedorganic layers were washed with brine, dried over Na₂SO₄, andconcentrated to afford the title compound. ¹H NMR (CDCl₃ 400 MHz) δ 7.08(t, 1H), 6.95 (d, 1H), 6.81 (d, 1H), 3.66 (s, 1H), 3.52-3.56 (m, 4H),2.82 (t, 2H), 1.90-1.94 (m, 4H), 1.76-1.84 (m, 2H).

Step 4:1-[3-(5-Chloro-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)isoxazol-5-yl]-1,3-dihydro-2H-imidazol-2-oneTo a solution of3-(5-chloro-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)isoxazol-5-amine(790 mg, 2.47 mmol), DMAP (30 mg, 0.247 mmol) and pyridine (215 mg, 2.72mmol) in anhydrous DCM (10 mL) was added phenyl carbonochloridate (464mg, 2.97 mmol) in portions at 0° C. Then the mixture was stirred at roomtemperature overnight, washed successively with saturated citric acidsolution (3 mL), sat. NaHCO₃ (3 mL) and brine, dried over Na₂SO₄ andconcentrated. The resulting crude product was purified on silic gel(PE/EA=5/1) to affordphenyl[3-(5-chloro-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)isoxazol-5-yl]carbamate.

To a solution ofphenyl[3-(5-chloro-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)isoxazol-5-yl]carbamate(410 mg, 0.93 mmol) in DMSO (5 mL) was added 2,2-dimethoxyethanamine(117 mg, 1.12 mmol). The mixture was stirred at 60° C. for 3 hours, thendiluted with water (20 mL), and extracted with EtOAc (7 mL×2). Thecombined organic layers were washed with brine (5 mL), dried over Na₂SO₄and concentrated to afford crudeN-[3-(5-chloro-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)isoxazol-5-yl]-N′-(2,2-dimethoxyethyl)urea.

A mixture ofN-[3-(5-chloro-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)isoxazol-5-yl]-N′-(2,2-dimethoxyethyl)urea(515 mg, 1 mmol) in HCOOH (6 mL) was stirred at 75° C. for 2 hours. Thevolatile materials were removed in vacuo. The resulting residue wasdiluted with water (3 mL), adjusted to pH 8 with sat. NaHCO₃, andextracted with EtOAc (4 mL×3). The combined organic layers were washedwith brine (10 mL), dried over Na₂SO₄ and concentrated. The resultingresidue was purified on silica gel (PE/EA=1/1) to afford the titlecompound. ¹H NMR (CDCl₃ 400 MHz) δ 8.87 (s, 1H), 7.05 (t, 1H), 6.95 (t,1H), 6.77-6.83 (m, 2H), 6.43-6.45 (m, 1H), 6.23 (s, 1H), 3.54-3.58 (m,2H), 3.32-3.39 (m, 2H), 2.79 (t, 2H), 1.84-1.87 (m, 4H), 1.67-1.75 (m,2H).

Step 5:{3-[3-(5-Chloro-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)isoxazol-5-yl]-2-oxo-2,3-dihydro-1H-imidazol-1-yl}aceticacid To a solution of1-[3-(5-chloro-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)isoxazol-5-yl]-1,3-dihydro-2H-imidazol-2-one(230 mg, 0.596 mmol) in MeCN (5 mL) was added K₂CO₃ (164 mg, 1.192 mmol)and ethyl 2-bromoacetate (148 mg, 0.89 mmol). The mixture was stirred at80° C. over 8 hours and filtered. The filtrate was concentrated andpurified on silica gel with PE/EtOAc to affordethyl{3-[3-(5-chloro-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)isoxazol-5-yl]-2-oxo-2,3-dihydro-1H-imidazol-1-yl}acetate.

To a solution ofethyl{3-[3-(5-chloro-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)isoxazol-5-yl]-2-oxo-2,3-dihydro-1H-imidazol-1-yl}acetate(180 mg, 0.38 mmol) in THF (5 mL) was added 1 M LiOH (1.5 mL). Themixture was stirred at room temperature for 2 hours. The solvent wasevaporated under vacuum. The resulting residue was diluted with water (4mL), adjusted to pH 3 with 1 M HCl, and filtered to afford the titlecompound. ¹H NMR (CD₃OD 400 MHz) δ7.07 (t, 1H), 6.92-6.96 (m, 2H),6.78-6.81 (m, 1H), 6.73 (d, 1H), 6.27 (s, 1H), 4.45 (s, 2H), 3.53-3.56(m, 2H), 3.29-3.35 (m, 2H), 2.80 (t, J=7 Hz, 2H), 1.73-1.91 (m, 6H).

Example 67

{3-[3-(3,4-Dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)isoxazol-5-yl]-2-oxo-2,3-dihydro-1H-imidazol-1-yl}aceticacid

Step 1: 3,4-Dihydrospiro[chromene-2,4′-piperidine] TFA salt A mixture oftert-butyl 4-oxopiperidine-1-carboxylate (29.27 g, 0.147 mol),pyrrolidine (14.6 g, 0.2 mol) and 2′-hydroxyacetophenone (20 g, 0.147mol) in MeOH (300 mL) was refluxed for 1 hour. After cooling to roomtemperature, the solvent was removed in vacuo. The residue was dilutedwith EtOAc (500 mL) and washed with water (2×500 mL). The organic phasewas dried over anhydrous sodium sulfate and concentrated under vacuum.The resulting residue was purified by silica gel chromatography withPE/EtOAc to give tert-butyl4-oxo-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidine]-1′-carboxylate asa white solid.

To a solution of tert-butyl4-oxo-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidine]-1′-carboxylate (15g, 47 mmol) in MeOH (150 mL) was added NaBH₄ (1.88 g, 49 mmol)portionwise at 25° C. over 30 min. The resulting mixture was stirred for2 hours at room temperature, then quenched by the addition of 50 mL ofwater. The resulting mixture was extracted with ethyl acetate (100mL×2). The combined organic layers were washed with water (100 mL×2),dried over anhydrous sodium sulfate, and concentrated under vacuum togive tert-butyl4-hydroxy-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidine]-1′-carboxylateas a white solid.

To a mixture of tert-butyl4-hydroxy-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidine]-1′-carboxylate(11.4 g, 43.8 mmol) in TFA (140 mL) was added triethylsilane (21 g, 180mmol). The resulting mixture was stirred at 80° C. for 5 hours, and thenconcentrated in vacuo. The resulting residue was swished with Et₂O,filtered and dried to give the title compound as a white solid. ¹H NMR(DMSO-d6 400 MHz) δ 7.05-7.07 (m, 2H), 6.77-6.83 (m, 2H), 3.15-3.19 (m,2H), 3.01-3.07 (m, 2H), 2.70-2.73 (m, 2H), 1.73-1.86 (m, 6H).

Step 2:{3-[3-(3,4-Dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)isoxazol-5-yl]-2-oxo-2,3-dihydro-1H-imidazol-1-yl}aceticacid The title compound was prepared in a similar manner as describedfor Example 66 from 3,4-dihydrospiro[chromene-2,4′-piperidine] TFA saltand 3-bromo-4,5-dihydroisoxazole-5-carboxylate. ¹H NMR (CD₃OD 400 MHz) δ6.94-6.96 (m, 2H), 6.82 (d, 1H), 6.70 (t, 2H), 6.61 (d, 1H), 6.17 (s,1H), 4.25 (s, 2H), 3.44 (d. 2H), 3.21-3.28 (m, 2H), 2.71 (t, 2H),1.73-1.78 (m, 4H), 1.61-1.68 (m, 2H).

Example 68

{3-[2-(5-Chloro-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3-thiazol-5-yl]-2-oxo-2,3-dihydro-1H-imidazol-1-yl}aceticacid

Step 1:1′-(5-Bromo-1,3-thiazol-2-yl)-5-chloro-3,4-dihydrospiro[chromene-2,4′-piperidine]A mixture of 2,5-dibromothiazole (0.975 g, 4.01 mmol),5-chloro-3,4-dihydrospiro[chromene-2,4′-piperidine] HCl salt (1 g, 3.65mmol) and DBU (1.3 mL, 8.62 mmol) in DMF (15 mL) was heated at 120° C.for 16 h. After cooling, the mixture was diluted with water andextracted with CH₂Cl₂. The CH₂Cl₂ extract was washed with water (3×),dried (Na₂SO₄) and concentrated. The resulting residue was dissolved inCH₂Cl₂ and passed through a short silica pad (eluting with CH₂Cl₂/EtOAc(1:1). After evaporation of the filtrate, the resulting residue wasswished with Et₂O, filtered and dried to give the title compound as abeige powder.

Step 2:Ethyl{3-[2-(5-chloro-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3-thiazol-5-yl]-2-oxo-2,3-dihydro-1H-imidazol-1-yl}acetateTo a 2-dram vial was added1′-(5-bromo-1,3-thiazol-2-yl)-5-chloro-3,4-dihydrospiro[chromene-2,4′-piperidine](250 mg, 0.625 mmol), ethyl (2-oxo-2,3-dihydro-1H-imidazol-1-yl)acetate(117 mg, 0.67 mmol), potassium phosphate tribasic (266 mg, 1.25 mmol)and copper(i) iodide (40 mg, 0.21 mmol) in dioxane (3 mL), followed byN,N′-dimethylethylenediamine (45 μL, 0.422 mmol). The mixture wasstirred at 90° C. for 4 h. After cooling, the mixture was diluted withwater (˜2 mL) and EtOAc, filtered through Celite™ and the filter cakewas washed with EtOAc. The combined EtOAc filtrates were concentrated invacuo. The resulting residue was purified by Combi-Flash™ (10 g, 30-80%EtOAc in hexanes for 20 min, 30 mL/min, 20 mL/fraction) to give thetitle compound as a white solid.

Step 3:{3-[2-(5-Chloro-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3-thiazol-5-yl]-2-oxo-2,3-dihydro-1H-imidazol-1-yl}aceticacid To a solution of ethyl13-[2-(5-chloro-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3-thiazol-5-yl]-2-oxo-2,3-dihydro-1H-imidazol-1-yl}acetate(140 mg, 0.29 mmol) in THF (4 mL) and MeOH (1 mL) was added 1N NaOH (0.6mL, 0.60 mmol). The mixture was stirred for 15 min, then diluted withwater and acidified with 1N HCl. The resulting white precipitate wascollected, and washed with water and Et₂O to give the title compound asa white powder. ¹H NMR (500 MHz, acetone-d₆): δ 7.20 (s, 1H), 7.15 (t,1H), 6.99 (d, 1H), 6.89-6.84 (m, 2H), 6.75 (d, 1H), 4.49 (s, 2H), 3.81(d, 2 H), 3.48-3.39 (m, 2H), 2.80 (m, 2H), 2.01-1.78 (m, 6H). MS: m/z461 (MH⁺).

Example 69

{5-[2-(5-Chloro-4-fluoro-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3-thiazol-5-yl]-2H-tetrazol-2-yl}aceticacid

Step 1:Ethyl{5-[2-(5-chloro-4-fluoro-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3-thiazol-5-yl]-2H-tetrazol-2-yl}acetateTo a solution oftert-butyl{5-[2-(5-chloro-4-oxo-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3-thiazol-5-yl]-2H-tetrazol-2-yl}acetatefrom Example 14, step 1 (200 mg, 0.4 mmol) in THF (8 mL) was added NaBH₄(5.7 mg, 0.149 mmol). The mixture was stirred at room temperature for 2hours, quenched with water (10 mL), and extracted with EtOAc (10 mL×2).The combined organic layers were washed with 10 mL of brine, dried overNa₂SO₄, concentrated and purified by PRE-TLC to affordethyl{5-[2-(5-chloro-4-hydroxy-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3-thiazol-5-yl]-2H-tetrazol-2-yl}acetateas white solid.

To a solution ofethyl{5-[2-(5-chloro-4-hydroxy-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3-thiazol-5-yl]-2H-tetrazol-2-yl}acetatefrom above (88 mg, 0.179 mmol) in anhydrous DCM (2 mL) was added DAST(116 mg, 0.718 mmol) at −78° C. The mixture was stirred at −78° C. for 1hour, then at room temperature overnight. The volatile materials wereremoved, and the resulting residue was purified by preparative TLC(PE/EA=1/1) to afford the title compound as a colorless oil. ¹H NMR(CDCl₃ 400 MHz) δ 7.92 (s, 1H), 7.23 (s, 1H), 7.05 (d, 1H), 6.87 (d,1H), 5.74-5.87 (m, 1H), 5.38 (s, 2H), 4.28 (q, 2H), 4.00 (d, 1H),3.69-3.79 (m, 2H), 3.36-3.43 (m, 1H), 2.34-2.46 (m, 2H), 2.02-2.17 (m,4H), 1.38 (t, 3H).

Step 2:{5-[2-(5-Chloro-4-fluoro-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3-thiazol-5-yl]-2H-tetrazol-2-yl}aceticacid The title compound was prepared in a similar manner as thatdescribed for Example 9 Step 2 fromethyl{5-[2-(5-chloro-4-fluoro-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3-thiazol-5-yl]-2H-tetrazol-2-yl}acetate.¹H NMR (CD₃OD 400 MHz) δ 7.86 (s, 1H), 7.28-7.32 (m, 1H), 7.06 (d, 1H),6.93 (d, 1H), 5.82 (dd, 1H), 5.58 (s, 2H), 3.95-3.99 (m, 1H), 3.72-3.81(m, 2H), 3.41-3.48 (m, 1H), 2.48 (t, 1H), 2.31 (d, 1H), 2.23-2.29 (m,1H), 2.07-2.13 (m, 2H), 1.86-1.98 (m, 1H).

Example 70

{5-[5-(5-Chloro-4-fluoro-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3,4-thiadiazol-2-yl]-2H-tetrazol-2-yl}aceticacid

The title compound was prepared in a similar as described for Example 69from{5-[5-(5-chloro-4-oxo-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3,4-thiadiazol-2-yl]-2H-tetrazol-2-yl}aceticacid (Example 13). ¹H NMR (CD₃OD 400 MHz) δ 7.28 (t, 1H), 7.04 (d, 1H),6.92 (d, 1H), 5.80 (d, 1H), 5.58 (s, 2H), 3.97 (d, 1H), 3.77-3.86 (m,2H), 3.52-3.55 (m, 1H), 2.44-2.52 (m, 1H), 1.97-2.21 (m, 5H).

Example 71

{5-[2-(5-Chloro-3-methyl-4-oxo-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3-thiazol-5-yl]-2H-tetrazol-2-yl}aceticacid

Step 1: tert-Butyl5-chloro-3-methyl-4-oxo-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidine]-1′-carboxylateTo a solution of LiHMDS (0.37 mL, 0.37 mmol, 1.0 M/THF) in THF (0.3 mL)at −78° C. was added tert-butyl5-chloro-4-oxo-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidine]-1′-carboxylate(Intermediate 1, step 2), and (100 mg, 0.29 mmol) in THF (0.8 mL) underArgon. After stirring for 30 min at −78° C., the solution was warmed to−20° C., and stirred for 1 h. A cooled solution of methyl iodide (122mg, 0.86 mmol) and HMPA (0.15 mL, 0.86 mmol) in THF (0.6 mL) was addeddropwise via cannula, and the reaction mixture was stirred at −20° C.After 2 h, the reaction was quenched with saturated aqueous ammoniumchloride (30 mL), warmed to room temperature, stirred for 30 min, andthen extracted with EtOAc (20 mL×3). The combined organic extracts werewashed with saturated aqueous ammonium chloride (20 mL) and saturatedaqueous sodium chloride (20 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The resulting residue was purifiedby preparative TLC (PE/EtOAc) to give the title compound.

Step 2: 5-Chloro-3-methylspiro[chromene-2,4′-piperidin]-4(3H)-onehydrochloride A mixture of tert-butyl5-chloro-3-methyl-4-oxo-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidine]-1′-carboxylate(600 mg, 1.64 mmol) in HCl/dioxane (10 mL, 8 M) was stirred at roomtemperature for 2 h, and then Et₂O (10 mL) was added to the mixture. Theresulting precipitate was collected by filtration, washed with 10 mLEt₂O, and dried in vacuo to give title compound. ¹H NMR (CDCl₃ 400 MHz):δ 9.74 (br, 2H), 7.38 (t, 1H), 7.08 (d, 1H), 6.93 (d, 1H), 3.27-3.41 (m,4H), 2.73-2.79 (m, 1H), 2.27-2.34 (m, 1H), 2.03-2.17 (m, 3H), 1.22 (d,3H).

Step 3:tert-Butyl{5-[2-(5-chloro-3-methyl-4-oxo-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3-thiazol-5-yl]-2H-tetrazol-2-yl}acetateTo a solution of5-chloro-3-methylspiro[chromene-2,4′-piperidin]-4(3H)-one hydrochloride(0.2 g, 0.664 mmol) andtert-butyl[5-(2-bromo-1,3-thiazol-5-yl)-2H-tetrazol-2-yl]acetate,Intermediate 3, (0.23 g, 0.664 mmol) in DMF (4 mL) was added K₂CO₃(0.366 g, 2.56 mmol) under a nitrogen atmosphere. The mixture wasstirred at 65° C. for 5 h. After cooling, the resulting precipitate wasremoved by filtration and the filtrate was concentrated in vacuo. Theresulting residue was extracted with EtOAc (10 mL×3). The combinedorganic layers were washed with brine (5 mL), dried over anhydrousNa₂SO₄, filtered and purified by silica gel chromatography (PE/EtOAc) togive title compound.

Step 4:{5-[2-(5-Chloro-3-methyl-4-oxo-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3-thiazol-5-yl]-2H-tetrazol-2-yl}aceticacid The title compound was prepared in a similar manner as describedabove for step 2 of this example fromtert-butyl{5-[2-(5-chloro-3-methyl-4-oxo-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3-thiazol-5-yl]-2H-tetrazol-2-yl}acetatewith HCl in dioxane. ¹H NMR (CD₃OD 400 MHz): δ 7.75 (s, 1H), 7.34-7.38(m, 1H), 6.96-7.00 (m, 2H), 5.46 (s, 2H), 3.83-3.87 (m, 2H), 3.39-3.49(m, 2H), 2.70-2.76 (m, 1H), 1.90-2.03 (m, 3H), 1.72-1.88 (m, 1H), 1.12(d, 3H).

Example 72

{4-[5-(5-Chloro-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3,4-thiadiazol-2-yl]-1H-1,2,3-triazol-1-yl}aceticacid

Step 1: Ethyl[4-(tributylstannyl)-1H-1,2,3-triazol-1-yl]acetate Amixture of ethyl azidoacetate (1.72 g, 13.3 mmol) andtributyl(ethynyl)stannane (4.20 g, 13.3 mmol) in 30 mL of anhydroustoluene was refluxed for 24 hours. After removing the solvent, theresidual was purified by silica gel column chromatography (PE/EA=15:1)to afford the title compound. ¹HNMR (CDCl3 400 MHz) δ 7.53 (s, 1H), 5.13(s, 2H), 4.17 (q, 2H), 1.56 (m, 6H), 1.20-1.28 (m, 9H), 1.03-1.07 (m,6H), 0.75-0.82 (m, 9H). M+1: 444 and 446.

Step 2:5-(5-Chloro-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3,4-thiadiazol-2-amineTo a solution of the5-chloro-3,4-dihydrospiro[chromene-2,4′-piperidine], TFA salt ofIntermediate 1, (0.6 g, 1.8 mmol), and 5-bromo-1,3,4-thiadiazol-2-amine(0.32 g, 1.8 mmol) in DMF (12 mL) was added K₂CO₃ (0.75 g, 5.4 mmol)under a nitrogen atmosphere. The mixture was stirred at 65° C. for 2hours. After cooling, the resulting precipitate was removed byfiltration and the filtrate was concentrated in vacuo. Then the residuewas extracted with EtOAc. The combined organic layers were washed withbrine, dried over anhydrous Na₂SO₄, filtered and purified by silica gelchromatography PE/EtOAc to give the title compound.

Step 3:1′-(5-Bromo-1,3,4-thiadiazol-2-yl)-5-chloro-3,4-dihydrospiro[chromene-2,4′-piperidine]A mixture of CuBr₂ (0.34 g, 1.54 mmol) and anhydrous CH₃CN (10 ml) waspurged with argon and cooled to 0° C. with an ice bath, then t-BuONO(0.207 g, 2 mmol) was added dropwise. The resulting mixture was stirredat 0° C. for 15 min, and then treated with5-(5-chloro-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3,4-thiadiazol-2-amine(0.45 g, 1.339 mmol). The cooling bath was removed and the mixture wasstirred at room temperature for 3 h. The mixture was diluted withaqueous HCl (10 mL, 1N) and extracted with EtOAc (20 mL×3). The combinedorganic layers were washed with brine and dried over Na₂SO₄, andconcentrated in vacuo to afford the title compound.

Step 4:Ethyl{4-[5-(5-chloro-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3,4-thiadiazol-2-yl]-1H-1,2,3-triazol-1-yl}acetateA mixture of1′-(5-bromo-1,3,4-thiadiazol-2-yl)-5-chloro-3,4-dihydrospiro[chromene-2,4′-piperidine](400 mg, 1 mmol),ethyl[4-(tributylstannyl)-1H-1,2,3-triazol-1-yl]acetate (625 mg, 1.4mmol), Pd(PPh₃)₄ (115 mg, 0.1 mmol) in DMF (10 ml) was stirred at 80° C.for 8 h under Argon. After cooling, the mixture was diluted with waterand extracted with EtOAc (20 mL×2). The combined organic layers wereconcentrated in vacuo, and the resulting residue was purified bypreparative TLC to give the title compound. ¹H NMR (CDCl₃ 400 MHz) δ8.23 (s, 1H), 7.06 (t, 1H), 6.96 (d, 1H), 6.76 (d, 1H), 5.22 (s, 2H),4.26-4.32 (m, 2H), 3.84-3.88 (m, 2H), 3.59-3.66 (m, 2H), 2.79-2.83 (m,2H), 1.96-1.97 (m, 2H), 1.89-1.92 (m, 2H), 1.78-1.83 (m, 2H), 1.36 (t,3H).

Step 5:{4-[5-(5-Chloro-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3,4-thiadiazol-2-yl]-1H-1,2,3-triazol-1-yl}aceticacid The title compound was prepared in a similar manner as thatdescribed for Example 9 Step 2 fromethyl{4-[5-(5-chloro-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3,4-thiadiazol-2-yl]-1H-1,2,3-triazol-1-yl}acetate.¹H NMR (DMSO-d₆, 400 MHz) δ 8.60 (s, 1H), 7.15 (t, 1H), 7.01 (d, 1H),6.85 (d, 1H), 5.13 (s, 2H), 3.76-3.80 (m, 2H), 3.49-3.55 (m, 2H),2.72-2.76 (m, 2H), 1.89-1.92 (m, 2H), 1.81-1.84 (m, 4H).

Example 73

{4-[2-(5-Chloro-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-1,3-thiazol-5-yl]-1H-1,2,3-triazol-1-yl}aceticacid The title compound was prepared in a similar manner as describedfor Example 72 (steps 4 and 5) from1′-(5-bromo-1,3-thiazol-2-yl)-5-chloro-3,4-dihydrospiro[chromene-2,4′-piperidine](from Example 68, step 1), andethyl[4-(tributylstannyl)-1H-1,2,3-triazol-1-yl]acetate (from Example72, step 1). ¹H NMR (DMSO-d₆, 400 MHz). δ8.37 (s, 1H), 7.58 (s, 1H),7.20 (t, 1H), 7.06 (d, 1H), 6.91 (d, 1H), 5.30 (s, 2H), 3.79-3.83 (m,2H), 2.77-2.81 (m, 2H), 1.95-1.98 (m, 2H), 1.83-1.90 (m, 4H).

Example 74

(5-{2-[4-Oxo-5-(trifluoromethyl)-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl]-1,3-thiazol-5-yl}-2H-tetrazol-2-yl)aceticacid

Step 1: 5-(Trifluoromethyl)spiro[chromene-2,4′-piperidin]-4(3H)-onehydrochloride The title compound was obtained by the treatment oftert-butyl4-oxo-5-(trifluoromethyl)-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidine]-1′-carboxylate(which was prepared in a similar fashion from 3-trifluoromethyl phenolas described for steps 1 and 3 of Intermediate 1) with 4M HCl indioxane.

Step 2: tert-Butyl(5-{2-[4-oxo-5-(trifluoromethyl)-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl]-1,3-thiazol-5-yl}-2H-tetrazol-2-yl)acetateTo a suspension of5-(trifluoromethyl)spiro[chromene-2,4′-piperidin]-4(3H)-onehydrochloride (310 mg, 0.96 mmol) andtert-butyl[5-(2-bromo-1,3-thiazol-5-yl)-2H-tetrazol-2-yl]acetate (346mg, 1 mmol) in NMP (3 mL) was added DBU (0.45 mL, 2.99 mmol). Themixture was stirred at 120° C. for 20 min. After cooling, the mixturewas diluted with water, acidified with 1M HCl and extracted with EtOAc.The EtOAc extract was washed with water (2×), dried (Na₂SO₄) andconcentrated in vacuo. The resulting residue was purified viaCombi-Flash™ (40 g, 20-60% EtOAc in hexanes for 15 min, 35 mL/min, 20mL/fraction) to afford the title compound as a foam. ¹H NMR (500 MHz,acetone-d₆): δ 7.85 (s, 1H), 7.80-7.73 (m, 1H), 7.52 (d, 2H), 5.57 (s,2H), 3.99 (d, 2 H), 3.65-3.56 (m, 2H), 3.02 (s, 2H), 2.21 (d, 2H),2.06-1.98 (m, 2H), 1.50 (s, 9H).

Step 3:(5-{2-[4-Oxo-5-(trifluoromethyl)-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl]-1,3-thiazol-5-yl}-2H-tetrazol-2-yl)aceticacid To a solution of tert-butyl(5-{2-[4-oxo-5-(trifluoromethyl)-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl]-1,3-thiazol-5-yl}-2H-tetrazol-2-yl)acetate(300 mg, 0.55 mmol) in THF (5 mL) and MeOH (1 mL) was added a solutionof 1M aqueous NaOH (1.1 mL, 1.1 mmol). After stirring for 10 min, themixture was acidified with 1M HCl, and extracted with EtOAc. The EtOAcextract was washed with water, dried (Na₂SO₄) and concentrated in vacuo.The resulting residue was purified by LC/MS using Max-RP™ (50×21 mmcolumn and a gradient of CH₃CN:0.6% formic acid 30-55% in 8.3 min, flowrate 25 mL/min) to give the title compound. ¹H NMR (500 MHz, DMSO-d₆): δ7.87 (s, 1 H), 7.79-7.72 (m, 1H), 7.50 (d, 2H), 5.62 (s, 2H), 3.86 (d,2H), 3.53-3.44 (m, 2H), 2.10-2.01 (m, 2H), 1.95-1.86 (m, 2H). MS; m/z495 (MH⁺).

Example 75

(5-{5-[5-(Trifluoromethyl)-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl]-1,3,4-thiadiazol-2-yl}-2H-tetrazol-2-yl)aceticacid

The title compound was prepared in a similar manner as described forExample 13, step 1 and followed by Example 74, step 3 starting from5-(trifluoromethyl)-3,4-dihydrospiro[chromene-2,4′-piperidine]hydrochloride,andtert-butyl[5-(5-bromo-1,3,4-thiadiazol-2-yl)-2H-tetrazol-2-yl]acetate,Intermediate 6. ¹H NMR (500 MHz, acetone-d₆): δ 7.37-7.26 (m, 2H), 7.20(d, 1H), 5.79 (s, 2H), 3.98 (d, 2H), 3.76-3.67 (m, 2H), 3.02 (s, 2H),2.04-1.93 (m, 6H). MS: m/z 482 (MH⁺).

Example 76

(5-{2-[5-(Trifluoromethyl)-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl]-1,3-thiazol-5-yl}-2H-tetrazol-2-yl)aceticacid The title compound was prepared in a similar manner as describedfor Example 74, steps 2 and 3 from5-(trifluoromethyl)-3,4-dihydrospiro[chromene-2,4′-piperidine]hydrochloride,and tert-butyl[5-(2-bromo-1,3-thiazol-5-yl)-2H-tetrazol-2-yl]acetate,Intermediate 3. ¹H NMR (500 MHz, acetone-d₆): δ 7.85 (d, 1H), 7.37-7.27(m, 2 H), 7.20 (d, 1H), 5.66 (s, 2H), 3.96 (d, 2H), 3.64-3.54 (m, 2H),3.01 (s, 3H), 2.05-1.95 (m, 4H), 1.95-1.86 (m, 2H). MS: m/z 481 (MH⁺).

Example 77

{5-[5-(5-Chloro-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)isoxazol-3-yl]-2H-tetrazol-2-yl}aceticacid

Step 1:5-Chloro-1′-ethanethioyl-3,4-dihydrospiro[chromene-2,4′-piperidine] To asuspension of 5-chloro-3,4-dihydrospiro[chromene-2,4′-piperidine] HClsalt (2 g, 7.3 mmol) and Et₃N (3 mL, 21.5 mmol) in CH₂Cl₂ (25 mL) wasadded acetyl chloride (0.7 mL, 9.8 mmol). After stirring for 1 h, themixture was diluted with water and extracted with CH₂Cl₂. The CH₂Cl₂extract was washed with diluted brine, dried (MgSO₄) and concentrated.The resulting residue was purified by Combi-Flash™ (40 g, 50-100% EtOAcin hexanes for 20 min, 40 mL/min, 18 mL/fraction) to give1′-acetyl-5-chloro-3,4-dihydrospiro[chromene-2,4′-piperidine] as an oil,which solidified on standing.

A mixture of1′-acetyl-5-chloro-3,4-dihydrospiro[chromene-2,4′-piperidine] (1.9 g,6.8 mmol) and Lawesson's reagent (3.6 g, 8.9 mmol) in CH₃CN (30 mL) washeated at 65° C. overnight. After cooling, the mixture was diluted withhexanes:Et₂O (1:1), and filtered through Celite™. The filtrate wasconcentrated and purified by Combi-Flash™ (40 g, 20-50% EtOAc in hexanesfor 20 min, 40 mL/min, 18 mL/fraction) to give the title compound.

Step 2: Ethyl4-(5-chloro-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-2-oxo-4-thioxobutanoateTo a suspension of NaH (1.5 g, 36.5 mmol) in THF (20 mL) was addeddiethyl oxalate (1 mL, 7.3 mmol), followed by a solution of5-chloro-P-ethanethioyl-3,4-dihydrospiro[chromene-2,4′-piperidine] (1.8g, 6.1 mmol) and dibenzo-18-C-6 (110 mg, 0.3 mmol) in THF (30 mL). Themixture was refluxed for 1 h and then poured into a 1:1 mixture ofEt₂O/1N HCl (200 mL) at −10° C. The reaction mixture was extracted withEtOAc. The organic layer was separated, dried (Na₂SO₄) and concentrated.The resulting residue was purified by chromatography on silica gel(hexanes:EtOAc, 5-40% over 15 min) to give the title compound as ayellow powder.

Step 3: Ethyl5-(5-chloro-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)isoxazole-3-carboxylateA mixture of ethyl4-(5-chloro-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)-2-oxo-4-thioxobutanoate(1 g, 2.5 mmol), hydroxylamine hydrochloride (211 mg, 2.5 mmol), andNaHCO₃ (276 mg, 3.3 mmol) in EtOH (20 mL) was refluxed for 2 h. Aftercooling, the mixture was diluted with water and extracted with EtOAc(3×). The combined EtOAc extracts were washed with brine, dried overNa₂SO₄, and concentrated. The resulting residue was purified bychromatography on silica gel (hexanes/EtOAc 5-40% in 15 min) to give thetitle compound as a yellow solid. ¹H NMR (400 MHz, acetone-d₆): δ7.16-7.08 (m, 1H), 6.99-6.92 (m, 1H), 6.85 (d, 1H), 5.57 (s, 1H), 4.30(q, 2H), 3.70-3.63 (m, 2H), 3.46-3.37 (m, 2H), 2.80 (m, 2H), 1.99-1.75(m, 6H), 1.35 (t, 3H).

Step 4:5-(5-Chloro-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)isoxazole-3-carboxamideTo a solution of ethyl5-(5-chloro-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)isoxazole-3-carboxylate(500 mg, 1.3 mmol) in THF (2 mL) and MeOH (1 mL) was added ammoniumhydroxide (1.5 mL, 38.5 mmol). The mixture was stirred at roomtemperature overnight. The volatile materials were removed in vacuo. Theresulting residue was diluted with water, acidified with 1M HCl andextracted with EtOAc. The EtOAc layer was washed with water, dried(MgSO₄) and concentrated. The resulting residue was swished with Et₂O,filtered and dried to give the title compound as a white solid. ¹H NMR(500 MHz, acetone-d₆): δ 7.15 (m, 2H), 6.99 (d, 1H), 6.88 (d, 1H), 6.80(s, 1H), 5.53 (s, 1H), 3.68 (d, 2H), 3.43 (t, 2H), 1.98 (t, 2H),1.95-1.78 (m, 4H).

Step 5:{5-[5-(5-Chloro-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)isoxazol-3-yl]-2H-tetrazol-2-yl}aceticacid The title compound was prepared in a similar manner as describedfor Example 2, steps 5 and 6, from5-(5-chloro-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl)isoxazole-3-carboxamide.¹H NMR (500 MHz, acetone-d₆): δ 7.19-7.12 (m, 1H), 7.00 (d, 1 H), 6.89(d, 1H), 5.80 (s, 1H), 5.76 (s, 2H), 3.77 (d, 2H), 3.55-3.45 (m, 2H),2.04-1.86 (m, 6H). MS: m/z 431 (MH⁺).

Example 78

(5-{2-[4-Hydroxy-5-(trifluoromethoxy)-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl]-1,3-thiazol-5-yl}-2H-tetrazol-2-yl)aceticacid The title compound was prepared, as a white solid, in the samemanner as described for Example 20, but using(5-{2-[4-oxo-5-(trifluoromethoxy)-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl]-1,3-thiazol-5-yl}-2H-tetrazol-2-yl)aceticacid (Example 21). LC-MS: m/z=513 (MH⁺). ¹H NMR (400 MHz, DMSO-d₆): δ13.80 (br s, 1 H), 7.89 (s, 1H), 7.33 (t, 1H), 6.95-6.88 (m, 2H), 5.70(s, 2H), 5.41 (d, 1H), 4.93-4.87 (m, 1 H), 3.89-3.80 (m, 1H), 3.80-3.72(m, 1H), 3.66-3.54 (m, 1H), 3.56-3.30 (m, 1H), 2.28 (d, 1H), 2.13 (dd,1H), 2.03-1.94 (m, 1H), 1.97-1.80 (m, 3H).

Example 79

(5-{2-[4-Hydroxy-5-(trifluoromethoxy)-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl]-1,3-thiazol-5-yl}-2H-tetrazol-2-yl)aceticacid-d₁ The title compound was prepared, as a white solid, in the samemanner as described for Example 20, but using(5-{2-[4-oxo-5-(trifluoromethoxy)-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl]-1,3-thiazol-5-yl}-2H-tetrazol-2-yl)aceticacid (Example 21) and NaBD₄. LC-MS: m/z=514 (MH⁺). ¹H NMR (400 MHz,DMSO-d₆): δ 13.82 (br s, 1H), 7.89 (s, 1H), 7.33 (t, 1H), 6.94-6.87 (m,2H), 5.70 (s, 2 H), 5.39 (s, 1H), 3.89-3.81 (m, 1H), 3.80-3.72 (m, 1H),3.66-3.53 (m, 1H), 3.53-3.28 (m, 1H), 2.28 (d, 1H), 2.12 (d, 1H), 1.99(d, 1H), 1.94-1.80 (m, 3H).

Example 80

(5-{2-[5-(Trifluoromethoxy)-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl]-1,3-thiazol-5-yl}-2H-tetrazol-2-yl)aceticacid-d₂ The title compound was prepared, as a white solid, through 2synthetic steps in the same manner as described for Example 21, butusing5-(trifluoromethoxy)-3,4-dihydrospiro[chromene-2,4′-piperidinium]chloride-d₂(Intermediate 20) in step 1. LC-MS: m/z=499 (MH⁺). ¹H NMR (400 MHz,DMSO-d₆): δ 13.81 (br s, 1H), 7.89 (s, 1H), 7.25 (t, 1H), 6.94-6.87 (m,2H), 5.70 (s, 2H), 3.89-3.78 (m, 2H), 3.56-3.44 (m, 2H), 1.91-1.74 (m,6H).

Example 81

(5-{2-[5-(Trifluoromethoxy)-1′H-spiro[chromene-2,4′-piperidin]-1′-yl]-1,3-thiazol-5-yl}-2H-tetrazol-2-yl)aceticacid The title compound was prepared, as a white solid, through 2synthetic steps in the same manner as described for Example 21, butusing 5-(trifluoromethoxy)spiro[chromene-2,4′-piperidinium]chloride(Intermediate 19) in step 1. LC-MS: m/z=495.0 (MH⁺). ¹H NMR (400 MHz,DMSO-d₆): δ 13.78 (br s, 1H), 7.89 (s, 1H), 7.30 (t, 1H), 7.01 (d, 1H),6.96 (d, 1H), 6.66 (d, 1H), 6.02 (d, 1H), 5.71 (s, 2H), 3.91-3.80 (m, 2H), 3.62-3.51 (m, 2H), 2.07-1.96 (m, 2H), 1.98-1.85 (m, 2H).

Example of a Pharmaceutical Formulation

As a specific embodiment of an oral composition of a compound of thepresent invention, 50 mg of the compound of any of the Examples isformulated with sufficient finely divided lactose to provide a totalamount of 580 to 590 mg to fill a size O hard gelatin capsule.

While the invention has been described and illustrated in reference tospecific embodiments thereof, those skilled in the art will appreciatethat various changes, modifications, and substitutions can be madetherein without departing from the spirit and scope of the invention.For example, effective dosages other than the preferred doses as setforth hereinabove may be applicable as a consequence of variations inthe responsiveness of the human being treated for a particularcondition. Likewise, the pharmacologic response observed may varyaccording to and depending upon the particular active compound selectedor whether there are present pharmaceutical carriers, as well as thetype of formulation and mode of administration employed, and suchexpected variations or differences in the results are contemplated inaccordance with the objects and practices of the present invention. Itis intended therefore that the invention be limited only by the scope ofthe claims which follow and that such claims be interpreted as broadlyas is reasonable.

1. A compound of structural formula I:

or a pharmaceutically acceptable salt thereof; wherein A is selectedfrom the group consisting of:

g is a single bond or a double bond; J and K are each independentlyselected from the group consisting of: S, O, NH, CH and CH₂, whereineach NH is unsubstituted or substituted with R^(g), and wherein each CHand CH₂ is unsubstituted or substituted with R², provided that when g isa single bond at least one of J and K is CH₂ unsubstituted orsubstituted with R², and further provided that when g is a double bondthen both J and K are CH; L and M are each independently selected fromthe group consisting of: S, O, NH and CH₂, wherein each NH isunsubstituted or substituted with R^(g), and wherein each CH₂ isunsubstituted or substituted with R²; T, U, V and W are eachindependently selected from N and CH, wherein each CH is unsubstitutedor substituted with R³, provided that at least two of T, U, V and W areCH; X is CH₂, wherein CH₂ is unsubstituted or substituted with R²; Y isindependently selected from the group consisting of: O, NH and CH₂,wherein each NH is unsubstituted or substituted with R^(g), and whereineach CH₂ is unsubstituted or substituted with R²; Z is independentlyselected from the group consisting of: S, S(O), S(O)₂, O, NH and CH₂,wherein each NH is unsubstituted or substituted with R^(g), and whereineach CH₂ is unsubstituted or substituted with R²; B is a 5 memberedheteroaryl ring containing 1, 2 or 3 heteroatoms selected from NH, O andS, wherein any CH is unsubstituted or substituted with one substituentselected from R^(a), and wherein any NH is unsubstituted or substitutedwith one substituent selected from R^(b); each R¹ is independentlyselected from the group consisting of: hydrogen, halogen, and C₁₋₃alkyl, wherein alkyl is unsubstituted or substituted with one to threesubstituents independently selected from halogen and hydroxy; each R² isindependently selected from the group consisting of: (1) hydrogen, (2)halogen, (3) oxo, (4) C₁₋₆ alkyl, (5) (CH₂)_(n)OR^(e), (6)(CH₂)_(n)N(R^(e))₂, (7) (CH₂)_(n)C≡N, (8) (CH₂)_(n)COR^(e), and (9)(CH₂)_(n)S(O)_(q)R^(e), wherein alkyl is unsubstituted or substitutedwith hydroxy or one to three halogens, and wherein any CH₂ in R² isunsubstituted or substituted with one to two groups independentlyselected from halogen, hydroxy, and C₁₋₄ alkyl unsubstituted orsubstituted with one to five fluorines; each R³ is independentlyselected from the group consisting of: (1) hydrogen, (2) halogen, (3)—C₁₋₆ alkyl, (4) —C₁₋₆ alkenyl, (5) —OC₁₋₆ alkyl, (6) (CH₂)_(n)OR^(e),(7) (CH₂)_(n)N(R^(e))₂, (8) (CH₂)_(n)C≡N, (9) (CH₂)_(n)COR^(e), and (10)(CH₂)_(n)S(O)_(q)R^(e), wherein alkyl is unsubstituted or substitutedwith one to three substituents selected from: hydroxy, halogen, C₁₋₄alkyl, C₃₋₆ cycloalkyl, C₂₋₅ cycloheteroalkyl, aryl, and heteroarylwherein alkyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl areunsubstituted or substituted with one to three substituents selectedfrom: halogen, hydroxy, and C₁₋₄ alkyl unsubstituted or substituted withone to five fluorines, and wherein any CH₂ in R³ is unsubstituted orsubstituted with one to two groups independently selected from halogen,hydroxy, and C₁₋₄ alkyl unsubstituted or substituted with one to fivefluorines; R⁴ is selected from the group consisting of:

each R^(a) is independently selected from the group consisting of: (1)hydrogen, (2) halogen, (3) cyano, (4) C₁₋₄ alkyl, unsubstituted orsubstituted with one to five fluorines, (5) C₁₋₄ alkoxy, unsubstitutedor substituted with one to five fluorines, (6) C₁₋₄ alkylthio,unsubstituted or substituted with one to five fluorines, (7) C₁₋₄alkylsulfonyl, (8) —CO₂H, (9) C₁₋₄ alkyloxycarbonyl, and (10) C₁₋₄alkylcarbonyl; each R^(b) is independently selected from the groupconsisting of: (1) hydrogen, and (2) C₁₋₄ alkyl, wherein alkyl isunsubstituted or substituted with one to five fluorines; each R^(c) isindependently selected from the group consisting of: (1) —(CH₂)_(m)CO₂H,(2) —(CH₂)_(m)CO₂C₁₋₃ alkyl, (3) —(CH₂)_(m)—NR^(b)—(CH₂)_(p)CO₂H, (4)—(CH₂)_(m)—NR^(b)—(CH₂)_(p)CO₂C₁₋₃ alkyl, (5)—(CH₂)_(m)—O—(CH₂)_(p)CO₂H, (6) —(CH₂)_(m)—O—(CH₂)_(p)CO₂C₁₋₃ alkyl, (7)—(CH₂)_(m)—S—(CH₂)_(p)CO₂H, and (8) —(CH₂)_(m)—S—(CH₂)_(p)CO₂C₁₋₃ alkyl,wherein any CH₂ in R^(c) is unsubstituted or substituted with one to twogroups independently selected from halogen, hydroxy, and C₁₋₄ alkylunsubstituted or substituted with one to five fluorines; each R^(d) isindependently selected from the group consisting of: (1) —(CH₂)_(n)CO₂H,(2) —(CH₂)_(n)CO₂C₁₋₃ alkyl, (3) —(CH₂)_(n)—NR^(b)—(CH₂)_(p)CO₂H, (4)—(CH₂)_(n)—NR^(b)—(CH₂)_(p)CO₂C₁₋₃ alkyl, (5)—(CH₂)_(n)—O—(CH₂)_(p)CO₂H, (6) —(CH₂)_(n)—O—(CH₂)_(p)CO₂C₁₋₃ alkyl, (7)—(CH₂)_(n)—S—(CH₂)_(p)CO₂H, and (8) —(CH₂)_(n)—S—(CH₂)_(p)CO₂C₁₋₃ alkyl,wherein any CH₂ in R^(d) is unsubstituted or substituted with one to twogroups independently selected from the group consisting of: halogen,hydroxy, and C₁₋₄ alkyl unsubstituted or substituted with one to fivefluorines; each R^(e) is independently selected from the groupconsisting of: (1) hydrogen, and (2) C₁₋₆ alkyl, wherein alkyl isunsubstituted or substituted with one to three substituentsindependently selected from the group consisting of: halogen, cyano,—C₁₋₄ alkoxy, —C₁₋₄ alkylthio, —C₁₋₄ alkylsulfonyl, —CO₂H, and —CO₂C₁₋₄alkyl; each R^(g) is independently selected from the group consistingof: (1) hydrogen, and (2) C₁₋₆ alkyl; m is an integer from 1 to 3; n isan integer from 0 to 3; p is an integer from 1 to 3; q is an integerfrom 1 to 2; t is an integer from 0 to 8; d is an integer from 0 to 2;and e is an integer from 0 to 2, provided that d+e is
 2. 2. The compoundof structural formula I according to claim 1

or a pharmaceutically acceptable salt thereof; wherein A is selectedfrom the group consisting of:

g is a single bond or a double bond; J and K are each independentlyselected from the group consisting of: S, O, NH, CH and CH₂, whereineach NH is unsubstituted or substituted with R^(g), and wherein each CHand CH₂ is unsubstituted or substituted with R², provided that when g isa single bond at least one of J and K is CH₂ unsubstituted orsubstituted with R², and further provided that when g is a double bondthen both J and K are CH; L and M are each independently selected fromthe group consisting of: S, O, NH and CH₂, wherein each NH isunsubstituted or substituted with R^(g), and wherein each CH₂ isunsubstituted or substituted with R²; T, U, V and W are eachindependently selected from N and CH, wherein each CH is unsubstitutedor substituted with R³, provided that at least two of T, U, V and W areCH; X is CH₂, wherein CH₂ is unsubstituted or substituted with R²; Y isindependently selected from the group consisting of: O, NH and CH₂,wherein each NH is unsubstituted or substituted with R^(g), and whereineach CH₂ is unsubstituted or substituted with R²; Z is independentlyselected from the group consisting of: S, S(O), S(O)₂, O, NH and CH₂,wherein each NH is unsubstituted or substituted with R^(g), and whereineach CH₂ is unsubstituted or substituted with R²; B is a 5 memberedheteroaryl ring containing 1, 2 or 3 heteroatoms selected from NH, O andS, wherein any CH is unsubstituted or substituted with one substituentselected from R^(a), and wherein any NH is unsubstituted or substitutedwith one substituent selected from R^(b); each R¹ is independentlyselected from the group consisting of: hydrogen, halogen, and C₁₋₃alkyl, wherein alkyl is unsubstituted or substituted with one to threesubstituents independently selected from halogen and hydroxy; each R² isindependently selected from the group consisting of: (1) hydrogen, (2)halogen, (3) oxo, (4) C₁₋₆ alkyl, (5) (CH₂)_(n)OR^(e), (6)(CH₂)_(n)N(R^(e))₂, (7) (CH₂)_(n)C≡N, (8) (CH₂)_(n)COR^(e), and (9)(CH₂)_(n)S(O)_(q)R^(e), wherein alkyl is unsubstituted or substitutedwith hydroxy or one to three halogens, and wherein any CH₂ in R² isunsubstituted or substituted with one to two groups independentlyselected from halogen, hydroxy, and C₁₋₄ alkyl unsubstituted orsubstituted with one to five fluorines; each R³ is independentlyselected from the group consisting of: (1) hydrogen, (2) halogen, (3)—C₁₋₆ alkyl, (4) —OC₁₋₆ alkyl, (5) (CH₂)_(n)OR^(e), (6)(CH₂)_(n)N(R^(e))₂, (7) (CH₂)_(n)C≡N, (8) (CH₂)_(n)COR^(e), and (9)(CH₂)_(n)S(O)_(q)R^(e), wherein alkyl is unsubstituted or substitutedwith hydroxy or one to three halogens, and wherein any CH₂ in R³ isunsubstituted or substituted with one to two groups independentlyselected from halogen, hydroxy, and C₁₋₄ alkyl unsubstituted orsubstituted with one to five fluorines; R⁴ is selected from the groupconsisting of:

each R^(a) is independently selected from the group consisting of: (1)hydrogen, (2) halogen, (3) cyano, (4) C₁₋₄ alkyl, unsubstituted orsubstituted with one to five fluorines, (5) C₁₋₄ alkoxy, unsubstitutedor substituted with one to five fluorines, (6) C₁₋₄ alkylthio,unsubstituted or substituted with one to five fluorines, (7) C₁₋₄alkylsulfonyl, (8) —CO₂H, (9) C₁₋₄ alkyloxycarbonyl, and (10) C₁₋₄alkylcarbonyl; each R^(b) is independently selected from the groupconsisting of: (1) hydrogen, and (2) C₁₋₄ alkyl, wherein alkyl isunsubstituted or substituted with one to five fluorines; each R^(e) isindependently selected from the group consisting of: (1) —(CH₂)_(m)CO₂H,(2) —(CH₂)_(m)CO₂C₁₋₃ alkyl, (3) —(CH₂)_(m)—NR^(b)—(CH₂)_(p)CO₂H, (4)—(CH₂)_(m)—NR^(b)—(CH₂)_(p)CO₂C₁₋₃ alkyl, (5)—(CH₂)_(m)—O—(CH₂)_(p)CO₂H, (6) —(CH₂)_(m)—O—(CH₂)_(p)CO₂C₁₋₃ alkyl, (7)—(CH₂)_(m)—S—(CH₂)_(p)CO₂H, and (8) —(CH₂)_(m)—S—(CH₂)_(p)CO₂C₁₋₃ alkyl,wherein any CH₂ in R^(e) is unsubstituted or substituted with one to twogroups independently selected from halogen, hydroxy, and C₁₋₄ alkylunsubstituted or substituted with one to five fluorines; each R^(d) isindependently selected from the group consisting of: (1) —(CH₂)_(n)CO₂H,(2) —(CH₂)_(n)CO₂C₁₋₃ alkyl, (3) —(CH₂)_(n)—NR^(b)—(CH₂)_(p)CO₂H, (4)—(CH₂)_(n)—NR^(b)—(CH₂)_(p)CO₂C₁₋₃ alkyl, (5)—(CH₂)_(n)—O—(CH₂)_(p)CO₂H, (6) —(CH₂)_(n)—O—(CH₂)_(p)CO₂C₁₋₃ alkyl, (7)—(CH₂)_(n)—S—(CH₂)_(p)CO₂H, and (8) —(CH₂)_(n)—S—(CH₂)_(p)CO₂C₁₋₃ alkyl,wherein any CH₂ in R^(d) is unsubstituted or substituted with one to twogroups independently selected from the group consisting of: halogen,hydroxy, and C₁₋₄ alkyl unsubstituted or substituted with one to fivefluorines; each R^(e) is independently selected from the groupconsisting of: (1) hydrogen, and (2) C₁₋₆ alkyl, wherein alkyl isunsubstituted or substituted with one to three substituentsindependently selected from the group consisting of: halogen, cyano,—C₁₋₄ alkoxy, —C₁₋₄ alkylthio, —C₁₋₄ alkylsulfonyl, —CO₂H, and —CO₂C₁₋₄alkyl; each R^(g) is independently selected from the group consistingof: (1) hydrogen, and (2) C₁₋₆ alkyl; m is an integer from 1 to 3; n isan integer from 0 to 3; p is an integer from 1 to 3; q is an integerfrom 1 to 2; t is an integer from 0 to 8; d is an integer from 0 to 2;and e is an integer from 0 to 2, provided that d+e is
 2. 3. The compoundof claim 1 wherein t is 0, d is 1, and e is 1; or a pharmaceuticallyacceptable salt thereof.
 4. The compound of claim 3 wherein T, U, V andW are CH, wherein CH is unsubstituted or substituted with R³; or apharmaceutically acceptable salt thereof.
 5. The compound of claim 1wherein R⁴ is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 6. The compound of claim5 wherein R⁴ is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 7. The compound of claim1 wherein R⁴ is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 8. The compound of claim5 wherein R⁴ is

or a pharmaceutically acceptable salt thereof.
 9. The compound of claim1 wherein B is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 10. The compound of claim1 wherein B is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 11. The compound of claim1 wherein A is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 12. The compound of claim11 wherein A is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 13. The compound of claim11 wherein r is 1 or 0; s is 0 or 1; R² is independently selected fromthe group consisting of: hydrogen, and oxo; and R³ is independentlyselected from the group consisting of: hydrogen, halogen, and —OCH₃; ora pharmaceutically acceptable salt thereof.
 14. The compound of claim 1wherein: A is selected from the group consisting of:

B is selected from the group consisting of:

R⁴ is

R³ is independently selected from the group consisting of: hydrogen,halogen, —OH, and —OC₁₋₆ alkyl; and s is 0 or 1; or a pharmaceuticallyacceptable salt thereof.
 15. The compound of claim 13 selected from thegroup consisting of:

or a pharmaceutically acceptable salt thereof.
 16. The compound of claim1 wherein: A is:

B-R⁴ is selected from the group consisting of:

each R³ is independently selected from the group consisting of: Cl, Br,—CH₃, —CF₃, and —OCF₃; R⁴ is:

and s is 1; or a pharmaceutically acceptable salt thereof.
 17. Thecompound of claim 1 selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 18. A pharmaceuticalcomposition comprising a compound of claim 1 in combination with apharmaceutically acceptable carrier. 19-23. (canceled)
 24. A method oftreating hyperglycemia, diabetes or insulin resistance in a mammal inneed thereof which comprises the administration to the mammal of atherapeutically effective amount of a compound of claim
 1. 25. A methodof treating a lipid disorder selected from the group consisting ofdyslipidemia, hyperlipidemia, hypertriglyceridemia,hypercholesterolemia, low HDL, and high LDL in a mammal in need thereofwhich comprises the administration to the mammal of a therapeuticallyeffective amount of a compound of claim 1.